Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE (www.oxfordhandbooks.com). © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

date: 19 January 2019

Tandem Pore Domain Potassium Channels

Abstract and Keywords

The KCNK gene family encodes two-pore-domain potassium (K2P) channels, which generate the background (“leak”) K+ currents that establish a negative resting membrane potential in cells of the nervous system. A pseudotetrameric K+-selective pore is formed by pairing channel subunits, each with two pore-domains, in homo- or heterodimeric conformations. Unique features apparent from high-resolution K2P channel structures include a domain-swapped extracellular cap domain, a lateral hydrophobic-lined fenestration connecting the lipid bilayer to the channel vestibule, and an antiparallel proximal C-terminal region that links the paired subunits and provides a site for polymodal channel modulation. Individual channels transition between open and closed states, with the channel gate located at the selectivity filter. In general, K2P channels display relatively modest voltage- and time-dependent gating, together with distinct single-channel rectification properties, that conspire to yield characteristic weakly rectifying macroscopic currents over a broad range of membrane potentials (i.e., background K+ currents). Of particular note, K2P channel activity can be regulated by a wide range of physicochemical factors, neuromodulators, and clinically useful drugs; a distinct repertoire of activators and inhibitors for different K2P channel subtypes endows each with unique modulatory potential. Thus, by mediating background currents and serving as targets for multiple modulators, K2P channels are able to dynamically regulate key determinants of cell-intrinsic electroresponsive properties. The roles of specific K2P channels in various physiological processes and pathological conditions are now beginning to come into focus, and this may portend utility for these channels as potential therapeutic targets.

Keywords: KCNK, K2P, leak, K+ current, TWIK, TREK, TRAAK, TASK, TALK, THIK, TRESK

Introduction

In the nervous system, maintaining a negative resting membrane potential—i.e., where the voltage across the plasma membrane is more negative on the intracellular side—is vital for cell function. For neurons, the electrochemical driving force provided by this negative potential allows for ion flux that underlies the rapid electrical and chemical signaling that drives all manner of behaviors; for glial cells, it permits the transmembrane transport of ions and signaling molecules that supports their various homeostatic functions.

A stable negative resting membrane potential represents a steady state condition, at which there is no net current due to ionic flux across the membrane resistance. This is not an equilibrium. The major ionic species (K+, Na+, Ca2+, Cl, HCO3, etc.) are differentially distributed across the cell membrane, with Nernst equilibrium potentials (Eion) that are not identical to the resting membrane potential (Em). Thus, a basal current for each species arises at steady state from ionic flux determined by the resulting electrochemical gradient (Em–Eion) across a finite membrane conductance, as defined by Ohm’s Law—essentially, there is some “leak” current for each ionic species. Additional currents derive from electrogenic ion pumps and transporters that maintain steady state ionic gradients. In sum, the steady state Em results from combined contributions of all ion currents, with the Em tending toward the Eion of the particular ion with the greatest relative resting conductance. For most cells, EK is a negative value (~–90 mV) due to the ~40-fold higher concentration of K+ ions inside the cell, and, because the resting conductance is highest for K+ ions, the cell obtains a negative resting Em near EK.

This basic concept—that cells possess a dominant “leak” K+ conductance under basal conditions—has been long understood. However, specific K+ channel candidates that might mediate this “leak” K+ conductance became available only with the advent of molecular cloning, initially with the identification of the voltage-gated (KV) and inwardly rectifying (Kir) family of K+ channels. Indeed, at membrane potentials near the resting Em, some KV channels display so-called window currents (persistent currents arising from overlap of activation and inactivation voltage ranges), and some Kir channels conduct constitutive current. Although these KV and Kir channels could conceivably underlie some “leak” K+ conductance, their voltage-dependent characteristics do not match the relatively voltage-independent characteristics expected of a classical “leak” conductance. Moreover, this more classical type of “leak” conductance had been observed in various cell types, often as a voltage-independent K+ current modulated by various physicochemical factors, neuromodulators, and clinically relevant drugs, but insensitive to classical blockers of KV and Kir channels (e.g., TEA [tetraethylammonium]) (Franks & Lieb, 1988; Nicoll, 1988; Nicoll, Malenka, & Kauer, 1990). A molecular basis for this alternative, more classical “leak” K+ conductance was ultimately realized with the cloning of the well-modulated and relatively voltage-independent K2P channels (Goldstein, Bockenhauer, O’Kelly, & Zilberberg, 2001; Goldstein, Price, Rosenthal, & Pausch, 1996; Goldstein, Wang, Ilan, & Pausch, 1998; Lesage, Guillemare, et al., 1996; Lesage & Lazdunski, 2000). It is now clear that this unique, structurally distinct family of “leak” K+ channels plays an important role in cellular and integrative physiological functions mediated by the brain and peripheral nervous system.

General Features of K2P Channels

The KCNK gene family encodes the “two pore-domain” K+ channels (K2P) that present unique structural and functional characteristics, distinctly different from those of KV and Kir channels. The mammalian KCNK gene family includes 15 members, which are distributed among six clades based on both sequence homology and shared functional properties of the encoded K2P channels (Fig. 1A). A numerical International Union of Basic and Clinical Pharmacology (IUPHAR) nomenclature was established for K2P channel subunits, which was based on the Human Genome Organization (HUGO) naming of the corresponding genes according to the chronological order of their identification (Goldstein et al., 2005). In addition to these formal naming schemes, the channels are often referred to by a set of acronyms that were derived from some salient physiological or pharmacological property (Enyedi & Czirjak, 2010; Feliciangeli, Chatelain, Bichet, & Lesage, 2015). Due to vagaries inherent in the naming process, including later recognition that channel genes originally found in other species were actually orthologues of a differently named human gene, the family now includes 15 genes (and corresponding channels) that are numbered from 1–18, where 8, 11, and 14 are omitted. Expression of K2P subunits individually in heterologous systems yielded functional channel activity for all but three (KCNK7, KCNK15, KCNK12); these “silent” genes are nevertheless expressed in some tissues, including brain, and recent work suggests that their activity may depend in certain circumstances on co-expression of another K2P subunit (Blin et al., 2014) Renigunta, Zou, Kling, Schlichthorl, & Daut, 2014).

Tandem Pore Domain Potassium ChannelsClick to view larger

Figure 1The KCNK gene family. A. Phylogeny analysis based on human K2P channel subunits. B. Weakly rectifying whole cell current-voltage (I–V) relationship obtained from mouse K2P2 expressed in HEK293 cells (adapted from Murbartian et al., 2005). Inset: Schematic of the general topology of K2P channel subunits. C. Structure of K2P10 determined by X-ray crystallography (in the “up-state” configuration). Note the prominent extracellular cap domain, and the fenestration through the channel vestibule.

From Dong et al., 2015. Reprinted with permission from AAAS.

Unique Structural Considerations

The primary structure of K2P channel subunits predicted a topology comprising cytoplasmic N- and C-termini, four transmembrane domains (M1 to M4), an extended M1P1 extracellular domain, a cytoplasmic M2M3 region, and two reentrant pore loops (P1, P2) (Fig. 1B, inset). The existence of two pore (P) loops in each subunit, rather than the single P-loop typical of other K+ channel subunits, accounts for their designation as two pore-domain K+ channels (K2P channels). For KV and Kir channels, the central pore of the protein is formed from four P-loops, one from each subunit, in a tetrameric configuration (Jiang et al., 2003). For K2P channels, therefore, a dimeric conformation in which each of the two subunits contributes two P-loops, allows assembly of a comparable pseudotetrameric channel pore (Brohawn, Campbell, & MacKinnon, 2013, 2014; Brohawn, del Marmol, & MacKinnon, 2012; Dong et al., 2015; Lolicato et al., 2017; McClenaghan et al., 2016; Miller & Long, 2012). It is now clear that K2P subunits can form channels as homodimers and heterodimers, combining with closely related subunits within their particular clade to yield channels with distinct properties (e.g., K2P3:K2P9; K2P2:K2P10) (Berg, Talley, Manger, & Bayliss, 2004; Blin et al., 2016; Kang, Han, Talley, Bayliss, & Kim, 2004; Lengyel, Czirjak, & Enyedi, 2016; Levitz et al., 2016)and/or allowing functional expression of otherwise silent subunits (K2P12 unsilenced by K2P13) (Blin et al., 2014) Renigunta et al., 2014); there have also been reports of heterodimeric channels formed between K2P subunits from different subgroups (K2P1:K2P3 or K2P1:K2P9; K2P1:K2P2) (Hwang et al., 2014; Wang et al., 2016; Zhou et al., 2009).

The characteristics expected for these channels from early biochemical and electrophysiological studies were subsequently verified by X-ray crystallographic analysis obtained for three different K2P channels (K2P1, K2P2 K2P4, K2P10) (Fig. 1C); these K2P channel structures revealed additional interesting features, some expected and others that had not been anticipated (Brohawn et al., 2013; Brohawn, Campbell, et al., 2014; Brohawn et al., 2012; Dong et al., 2015; Lolicato et al., 2017; McClenaghan et al., 2016; Miller & Long, 2012).

A large extracellular cap domain, not present in other K+ channels, is formed by the extended M1P1 loop. In the channel structures, the M1P1 domains of the two subunits were covalently linked at the peak of the cap via a cysteine–disulfide bridge, a covalent link that may stabilize the dimer, as predicted based on earlier biochemical and functional studies of K2P1 (Hwang et al., 2014; Lesage, Reyes, et al., 1996). The cap appears in all structures to date, but the disulfide is unlikely to be found in all K2P channels, because the relevant cysteine residues are not uniformly present (e.g., there is no analogous M1P1 cysteine in K2P3 or K2P9 subunits) (Goldstein et al., 2016). At the peak of the cap, a “domain swapping” is observed between the two subunits, such that outer pore helices from one subunit envelop inner pore helices from the other subunit; whether there is any functional significance to this unique arrangement remains to be clarified, but it has been observed in structures from different K2P channels. The extracellular cap blocks access of ions to the pore from directly overhead, but it overlays two pathways lined with negatively charged residues that are large enough to funnel hydrated K+ ions toward the pore.

The pore resembles that of other K+ channels even though it derives in K2P channels from a pseudotetrameric arrangement in which non-identical residues from P1 and P2 pore domains comprise the selectivity filter, and is formed within the unique domain-swapping arrangement mentioned here. A large vestibule below the selectivity filter is also characteristic of other K+ channels, although a unique feature is apparent in the K2P structure: a fenestration lined by hydrophobic residues provides access between the lipid bilayer and the vestibule, which may be occupied by lipids or ligands that modulate channel gating. The fenestration is apparent in K2P channel structures in a “down-state,” but not in an alternative “up-state,” reflecting conformational rearrangements around a hinge glycine in the subunit TM4 domains (Brohawn et al., 2013; Brohawn, Campbell, et al., 2014; Brohawn et al., 2012; Dong et al., 2015; Lolicato et al., 2017; McClenaghan et al., 2016; Miller & Long, 2012). The relationship between the down and up conformational states (i.e., either with or without the fenestration) and the conductive state of the channels remains to be firmly established.

At the cytoplasmic end of the pore, K2P channels do not possess the classical bundle-crossing gate that physically impedes ionic current in other K+ channels; rather, functional studies indicate that K2P channels remain accessible to cytoplasmic ions up to the level of the selectivity filter, even when the channel is closed (Piechotta et al., 2011). Thus, gating in K2P channels takes place at the selectivity filter itself.

A cytoplasmic domain emerging at the end of TM4 appears to run antiparallel to the lipid bilayer, and provides a structural link between subunits. Interestingly, this C-helix region of the channel is also implicated as a functionally important site for effects of various factors that modulate K2P channel function. At this point, defining a structural basis for coupling actions of this domain to selectivity-filter gating remains an area of active research (Bagriantsev, Clark, & Minor, 2012; Bagriantsev, Peyronnet, Clark, Honore, & Minor, 2011; Chemin, Patel, Duprat, Lauritzen, et al., 2005; Honore, 2007; Honore, Maingret, Lazdunski, & Patel, 2002; Lolicato et al., 2017).

Unique Functional Characteristics

Heterologous expression of K2P channel subunits revealed properties that were unlike those of the previously identified KV or Kir channels (Enyedi & Czirjak, 2010; Feliciangeli et al., 2015; Goldstein et al., 2001; Goldstein et al., 1998; Honore, 2007; Kim, 2005; Renigunta, Schlichthorl, & Daut, 2015; Talley, Sirois, Lei, & Bayliss, 2003). K2P channels invariably generated K-selective currents across a wide range of membrane potentials, including at negative potentials where neurons find themselves at rest or between action potentials (Fig. 1B). Thus, these K2P channels appeared well suited to provide a background K+ conductance to establish this negative resting membrane potential. In addition, a strong instantaneous K2P current component accompanied step changes in voltage, and the associated current-voltage plots typically deviated only weakly from an Ohmic (i.e., linear) relationship, especially in symmetrical K+ solutions. A more prominent, though still weak, rectification was obtained in physiological K+ solutions that could often be approximated by the Goldman-Hodgkin-Katz (GHK) equation that accounts for effects of asymmetrical K+ concentrations on ionic current. These latter considerations implied that K2P channels provided a background K+ current that also fit a classical expectation for a “leak” or “open-rectifier” current.

This characterization remains largely accurate in a description of general K2P channel properties, but it obscures some important details (see Renigunta et al., 2015). First, unitary recordings revealed that single K2P channels, like other self-respecting ion channels, undergo stochastic transitions between closed and open states; they are not simply open, K+-selective membrane pores. Second, some K2P channel currents show inward rectification rather than outward rectification (Lesage, Guillemare, et al., 1996), indicating that that they do not dutifully follow the dictates of Ohm’s Law for a voltage-independent open pore. Third, K2P channels show additional voltage dependence, both in the form of a time-dependent component of whole cell current that develops following changes in voltage step, and in voltage-dependent changes in single-channel open probability (PO) (Kim, Bang, & Kim, 1999; Renigunta et al., 2015; Schewe et al., 2016). The basis for this voltage-dependence in PO is unclear, since these channels do not possess a charged TM segment like the S4 domain that mediates voltage sensing in KV and other voltage-dependent ion channels; recent work suggests a novel ion-flux gating mechanism that derives from ion movement within the membrane electric field (Schewe et al., 2016). Thus, the whole cell GHK rectification observed in some K2P channels is actually a fortuitous consequence of the combination of single-channel rectification and voltage-dependent gating (Kim et al., 1999; Renigunta et al., 2015). These more complex underlying channel properties notwithstanding, the observation that K2P channels provide weakly rectifying macroscopic K+ currents across a wide range of membrane potentials remains valid, and they can thereby provide a “leak” K+ current in the cell membrane.

The classical leak current designation, at least as incorporated into equivalent electrical circuit models, envisions a static background conductance. However, several different modulatory mechanisms that impinge on K2P channels were identified essentially immediately upon their functional expression. It was also subsequently recognized that these channels may be molecular substrates for the various non-KV and non-Kir leak K+ currents that had been recorded in native cells upon stimulation by various physicochemical factors, neuromodulators, and clinically relevant drugs.

Here, we discuss the principal defining modulatory characteristics of the major subgroups of K2P channels, especially as they relate to specific nervous system functions of those channels. In some cases, the channels are most prominently expressed outside of the nervous system, and we touch on those only briefly for completeness. A number of additional, exhaustive reviews on K2P channel structure and function are also available (Enyedi & Czirjak, 2010; Feliciangeli et al., 2015; Goldstein et al., 2001; Goldstein et al., 1998; Honore, 2007; Kim, 2005; Renigunta et al., 2015; Sepulveda, Pablo Cid, Teulon, & Niemeyer, 2015; Talley et al., 2003).

Properties of K2P Channel Subgroups

TWIK Family

The TWIK (Tandem of P domains in a weak inwardly rectifying K+ channel) family includes K2P1 (TWIK-1), K2P6 (TWIK-2) and K2P7 (KCNK7). Among this group, small currents were initially obtained following heterologous expression of cloned K2P1 and K2P6 subunits in Xenopus oocytes (Lesage, Guillemare, et al., 1996; Patel et al., 2000; Salinas et al., 1999), both of which yielded weakly inwardly rectifying current-voltage (I-V) relationships that account for their common name; the currents from K2P6 were notable for their slow inactivation, an uncommon property in K2P channels (Patel et al., 2000). Functional currents have not yet been obtained from expression of recombinant KCNK7 subunits. K2P1 and the (so far) non-functional KCNK7 are both expressed throughout the nervous system (Lesage et al., 1997; Medhurst et al., 2001; Talley, Solorzano, Lei, Kim, & Bayliss, 2001); K2P6 is found mostly in the periphery (Medhurst et al., 2001), and will not be considered further.

K2P1 was the founding member of mammalian K2P channel family (Lesage, Guillemare, et al., 1996), and provided one of the initial high-resolution K2P structures (Miller & Long, 2012). However, there remains significant controversy and confusion as to the specific channel properties and physiological roles of K2P1. This uncertainty has arisen, in large part, from difficulties encountered by many groups in recording K2P1 channel currents in heterologous expression systems. In addition, knockout mice have not yet yielded any major insights into the K2P1 functions within the nervous system.

Various mechanisms have been advanced to explain the diminutive K2P1 channel currents. A dynamic covalent modification of membrane bound K2P1, involving the addition and removal of a small ubiquitin-like modulator (SUMO) adducts at Lys-274, was proposed to silence and activate the channel, respectively (Plant et al., 2010; Rajan, Plant, Rabin, Butler, & Goldstein, 2005); the de-sumoylated K2P1 channels showed GHK rectification rather than inward rectification (Rajan et al., 2005). The supporting evidence for this SUMO-based mechanism is compelling, although other laboratories have found the results difficult to replicate (Feliciangeli et al., 2007). An alternative (or additional) explanation for small K2P1 currents envisages constitutive, brisk, endocytic trafficking of the channel (Bichet et al., 2015; Feliciangeli et al., 2010). It was found that rapid retrieval of K2P1 channels from the plasma membrane occurred via a dynamin-mediated process requiring a C terminal di-isoleucine repeat of K2P1 (Feliciangeli et al., 2010); the process is regulated by Gαi/o-coupled receptors, which act to enhance membrane levels of K2P1 (Feliciangeli et al., 2010; Wang et al., 2016). Finally, a novel hydrophobic gating mechanism was suggested from molecular dynamic simulations based on the K2P1 structure (Aryal, Abd-Wahab, Bucci, Sansom, & Tucker, 2014). According to this model, a hydrophobic cuff within the pore leads to de-wetting of the inner cavity to impede ion permeation (Aryal et al., 2014); accordingly, in silico substitutions of polar residues at sites within that cuff were associated with water retention in the simulations (i.e., Leu-146, Leu-261), while, experimentally, the corresponding mutations yielded enhanced K2P1 currents (Aryal et al., 2014). Some combination of these mechanisms may account for the low activity of K2P1 channels in heterologous systems, and regulation of these dynamic processes could modulate K2P1 channel activity in native contexts.

In cerebellar granule neurons, for example, a fraction of background current was attributed to heterodimeric K2P1:K2P3 or K2P1:K2P9 channels that were silenced by sumoylation of the K2P1 subunit in the channels (Plant, Zuniga, Araki, Marks, & Goldstein, 2012). In some studies, a fraction of the large, linear, background K current found in astrocytes was attributed to K2P1 channels or to a K2P1:K2P2 heterodimer (Hwang et al., 2014; Wang et al., 2016; Zhou et al., 2009), with the latter reported to display a G protein (Gβγ) activation that permits astrocytic glutamate release via the channel (presumably via some ill-defined pore dilation mechanism that allows permeation by the large, anionic glutamate molecule through previously K+-selective pores) (Hwang et al., 2014; Woo et al., 2012). This work will need to be reconciled with other reports that K2P1 and K2P2 do not co-assemble (Blin et al., 2016; Plant et al., 2012), and with recent data from knockout mice indicating that astrocytic leak K+ currents do not require expression of either K2P1 or K2P2 subunits (Du et al., 2016); the latter may in part reflect a need for Gαi/o-coupled receptor activation to overcome intracellular retention of K2P1 in astrocytes (Wang et al., 2016).

A further unique feature described for K2P1 homodimeric channels involves dynamic ionic selectivity. Specifically, under conditions of low extracellular K+ or low pH, the channel slowly obtains a significant Na+ permeability that recovers with a similar slow time course (τ ~ 4–6 mins) (Chatelain et al., 2012; Chen, Chatelain, & Lesage, 2014; Ma, Zhang, & Chen, 2011). A conformational rearrangement within the K2P1 channel probably accounts for this dynamic ionic selectivity, perhaps due to actions on K2P1-specific residues within the selectivity filter or pore (Chatelain et al., 2012; Chen et al., 2014; Ma et al., 2011). The consequence is that K2P1 channels may have either a hyperpolarizing or a depolarizing influence on cell membranes, depending on the prevailing conditions. For example, removing extracellular K+ leads to a “paradoxical depolarization” in cardiac myocytes that is dependent on K2P1 expression, and attributed to its enhanced Na permeation in lower [K] (Chen et al., 2014; Ma et al., 2011). In addition, the membrane potential of astrocytes (and pancreatic β cells) from K2P1-knockout mice are more hyperpolarized than their wild-type counterparts, implying that the channel may usually provide a depolarizing current in these cells (Chatelain et al., 2012; Wang et al., 2016). This could be the case if K2P1, with a prominent Na+ selectivity in acidic endosomes, is recycled to the cell surface, and then rapidly retrieved again from the membrane before K+ selectivity can be restored by the more alkaline extracellular pH (Chatelain et al., 2012).

In sum, K2P1 and KCNK7 (but not K2P6) are widely expressed in the nervous system. The conditions that support functional channel activity of KCNK7 have not yet been defined. The properties of K2P1 have also been difficult to ascertain, due primarily to low functional channel expression in heterologous systems. Nonetheless, a number of distinctive features of K2P1 have been observed (e.g., sumoylation, receptor-modulated rapid endocytosis, pore de-wetting, dynamic ionic selectivity); these unique channel mechanisms imply that contributions of K2P1 to native neuronal and astrocytic membrane current may depend on prevailing physiological conditions, and that K2P1 may not always generate a K+-selective current.

TREK Family

The TREK (TWIK-related K+ channel) family includes three subunits: K2P2 (TREK-1), K2P4 (TRAAK; TWIK-related arachidonic acid-activated K+ channel), and K2P10 (TREK-2). The members of this K2P subgroup express well in heterologous systems and are arguably the best-studied group of K2P channels. These channels are considered as polymodal signal integrators since they are modulated by a whole host of different factors: temperature, stretch, pH, bioactive lipids, receptor-activated signaling pathways, and clinically useful drugs, like inhaled anesthetics and antidepressants (Honore, 2007).

The channels are active at negative membrane potentials and generally K+-selective (with the exception of some structural variants of TREK-1); they activate with modest time-dependence upon depolarization to yield an outwardly rectifying I–V relationship, which reflects a voltage-dependent single-channel open probability superimposed on either outwardly rectifying (K2P2) or inwardly rectifying unitary conductance (K2P4, K2P10) (Blin et al., 2016). They are widely expressed throughout the brain and are found in neurons of sensory and autonomic ganglia (Aller & Wisden, 2008; Gu et al., 2002; Kang & Kim, 2006; Medhurst et al., 2001; Talley et al., 2001).

Structural diversity among this K2P channel family arises from some common mechanisms, but also from some more unusual processes. First, splice variants with different expression patterns but similar functional properties were identified for K2P2 and K2P10 (Gu et al., 2002; Mirkovic & Wickman, 2011; Rinne et al., 2014). For K2P2, some alternative splice variants yield truncated forms of the protein that act in dominant negative fashion on full-length K2P2, probably by interfering with surface expression (Rinne et al., 2014; Veale, Rees, Mathie, & Trapp, 2010); for K2P10, the splice variants are differentially compatible with an alternative translation initiation described later (Staudacher et al., 2011). In addition, all members of this K2P clade can mix and match to form heterodimers with unique properties (Blin et al., 2016; Lengyel et al., 2016; Levitz et al., 2016). As mentioned before, there is also some evidence for promiscuity in these pairings, with K2P2 identified as coexisting with K2P1 in astrocyte channels (Hwang et al., 2014; Wang et al., 2016; Zhou et al., 2009); however, this has not been independently confirmed (Blin et al., 2016; Du et al., 2016; Plant et al., 2012).

A more surprising mechanism for generating channel diversity was discovered for both K2P2 and K2P10—specifically, alternative translation initiation (ATI). For these subunits, a suboptimal Kozak sequence around the most 5’ initiator methionine position allows ribosomal scanning to skip those start sites and initiate translation from a downstream methionine. This ATI process may be differentially regulated in the brain during development (Thomas, Plant, Wilkens, McCrossan, & Goldstein, 2008), and the N-terminally truncated ATI variants present with different single-channel properties (especially, distinct unitary conductance) (Simkin, Cavanaugh, & Kim, 2008; Thomas et al., 2008). For K2P2, the foreshortened ATI variant also exhibits an enhanced Na+ selectivity, such that its expression would yield a cationic “leak” channel promoting membrane depolarization (increased excitability), as opposed to the hyperpolarizing influence of the full-length K2P2 variant (Thomas et al., 2008). This change in ionic selectivity was not observed in ATI variants of K2P10 (Simkin et al., 2008).

The documented mechanisms of modulation for this well-studied subgroup of K2P channels are the most numerous and diverse; interestingly, although diverse, many of these modulatory mechanisms converge on the proximal C terminal domain that runs antiparallel to, and probably interacts with, the inner leaflet of the membrane bilayer to provide a contact point for transduction of conformational changes to affect the selectivity filter “gate” (Bagriantsev et al., 2012; Bagriantsev et al., 2011; Honore, 2007; Lolicato et al., 2017; Patel & Honore, 2002).

In terms of physicochemical mechanisms, all three channels in this subgroup are activated by membrane stretch and by increases in temperature, involving the proximal C-terminal region (Honore, 2007; Patel & Honore, 2002). The activation by temperature is apparent from ~24°C to 42°C, with a Q10~10 (Kang, Choe, & Kim, 2005; Maingret, Lauritzen, et al., 2000). The effects of negative pressure (or convex membrane curvature) are observed on channels expressed in cell-free patches or purified and incorporated into proteoliposomes (Brohawn, Campbell, et al., 2014; Brohawn, Su, & MacKinnon, 2014; Kang, Choe, Cavanaugh, & Kim, 2007; Maingret, Fosset, Lesage, Lazdunski, & Honore, 1999; Maingret, Patel, Lesage, Lazdunski, & Honore, 1999; Patel et al., 1998) (Berrier et al., 2013), suggesting direct effects of mechanical distortion on channel function; on the other hand, the modulation by temperature is lost in cell-free patches (Kang et al., 2005; Maingret, Lauritzen, et al., 2000).

Intracellular acidification strongly activates K2P2 and K2P10, via protonation of a glutamate residue located in the proximal C-terminal region of the channel (Kang et al., 2007; Maingret, Patel, et al., 1999); when activated by intracellular acidification, the effects of stretch and temperature are occluded (Honore et al., 2002). The channels are also sensitive to extracellular protons, via a titratable M1P1 loop histidine residue common to all these channels. However, acidification inhibits K2P2 and K2P4 while it activates K2P10; this differential modulation reflects electrostatic interactions of the common protonated histidine with nearby residues that are of opposite charge in the two channels (negative in K2P2 vs. neutral or positive in K2P10) (Sandoz, Douguet, Chatelain, Lazdunski, & Lesage, 2009) (Lesage & Barhanin, 2011).

The channels are also activated via proximal C terminal interactions with other proteins and various classes of lipids. For lipids, this includes polyunsaturated fatty acids (PUFAs), lysophospholipids (e.g., lysophosphatidylcholine), and phosphatidylinositol-4,5-bisphosphate (PIP2); the effects of lysophospholipids are apparently indirect, whereas activation by PUFAs and PIP2 is thought to be direct (Chemin, Patel, Duprat, Zanzouri, et al., 2005; Chemin, Patel, Duprat, Lauritzen, et al., 2005; Maingret, Patel, Lesage, Lazdunski, & Honore, 2000; Patel, Lazdunski, & Honore, 2001). The actions of arachidonate do not require breakdown via lipoxygenase or cyclooxygenase, but metabolism of PIP2 by phospholipase C (PLC) may contribute, in part, to reduced channel activity downstream of Gαq-coupled receptor signaling (Chemin et al., 2003; Chemin et al., 2007). Multiple proteins can interact within or near the proximal C terminal regulatory domain in K2P2 and K2P10 (but not K2P4) to affect channel function: A-kinase anchoring protein, AKAP150, binds to this region and fully activates the channels, occluding effects of other activators (arachidonate, stretch, pH) (Sandoz et al., 2006); microtubule-associated protein 2 (Mtap2) can also bind simultaneously to enhance surface expression (Sandoz et al., 2008). Together, the protein complexes aggregate signaling molecules to support dynamic modulation of channel function.

Physiologically, a number of G protein-coupled receptors (GPCRs) regulate activity of K2P2 and K2P10, but not K2P4; specifically, the channels are inhibited by Gαq- and Gαs-coupled receptors, and activated by Gαi-coupled receptors. For Gαq-coupled receptors, channel inhibition probably results from a combination of PLC-mediated breakdown of PIP2, a channel activator (Chemin et al., 2007), and a sequential mechanism whereby protein kinase C (PKC) phosphorylates K2P2 at Ser-333 to enable a subsequent inhibitory modification at Ser-300 within the proximal C terminal regulatory region (Murbartian, Lei, Sando, & Bayliss, 2005); in K2P10, the corresponding sites (Ser-326, Ser-359) contribute to GαqPCR modulation by protein kinase A (PKA) and PKC (Gu et al., 2002; Kang, Han, & Kim, 2006; Lesage, Terrenoire, Romey, & Lazdunski, 2000). Similarly, Gαs-coupled receptors mediate channel inhibition via PKA modification of the same phosphorylation sites (Murbartian et al., 2005), as does receptor-independent channel inhibition by the metabolic sensor, adenosine monophosphate–activated protein kinase (AMP kinase) (Kreneisz, Benoit, Bayliss, & Mulkey, 2009; Patel et al., 1998). Conversely, activation of K2P2 and K2P10 by Gαi-coupled receptors involves dephosphorylation at these sites, implying a constitutive level of phosphorylation-mediated channel inhibition under basal conditions (Cain, Meadows, Dunlop, & Bushell, 2008; Lesage et al., 2000).

Interestingly, various “off-target” actions of pharmacological agents on these channels might contribute to their clinically relevant therapeutic actions. For example, inhalational anesthetics activate K2P2 and K2P10 (but not K2P4) (Patel et al., 1999), providing ion channel substrates for the “leak” K+ channels underlying anesthetic-evoked membrane hyperpolarization in various neurons (along with K2P3, K2P9) (Franks & Lieb, 1988; Nicoll & Madison, 1982). In addition, these same channels are inhibited in a state-dependent manner by antidepressants like fluoxetine and paroxetine (Heurteaux et al., 2006; Kennard et al., 2005); the state-dependent binding of nor-fluoxetine, localized to the intramembrane fenestration in structural studies of K2P10, has been exploited to suggest structurally distinct open states associated with various activation mechanisms (Dong et al., 2015; McClenaghan et al., 2016). Further in this respect, K2P2 and K2P10 are inhibited by spadin, a peptide product from the neurotensin 3 receptor propeptide that itself has antidepressant actions (Mazella et al., 2010). These observations suggest a role for K2P2 and K2P10 in mediating effects of anesthetic and antidepressant drugs.

The widespread expression and extensive modulatory potential of this subgroup of channels suggested possible contributions to various physiological and pharmacological mechanisms, possibilities that have been tested using currently available genetic mouse models. With respect to the pharmacology discussed before, genetic deletion of K2P2 yielded reduced sensitivity to inhalational anesthetics and a depression-resistant phenotype (Heurteaux et al., 2004; Heurteaux et al., 2006); in K2P2-deleted mice, the antidepressant effects of fluoxetine and paroxetine were occluded, and the firing behavior of serotonergic neurons under baseline conditions in vivo resembled that of mice treated with antidepressants (Heurteaux et al., 2006).

The polymodal nature of channel activation, together with expression in sensory neurons, was reflected in exaggerated responses to mechanical and thermal stimuli in mice deleted for these channels, consistent with removal of an activated “leak” K+ channel that serves as an excitability “brake” in those cells (Alloui et al., 2006; Noel et al., 2009; Pereira et al., 2014). Likewise, acute siRNA-depletion of K2P10 from nociceptors caused membrane depolarization, enhanced spontaneous firing, and was associated with increased spontaneous pain in neuropathy models (Acosta et al., 2014). A contribution of K2P2 to generally limiting neuronal excitability was revealed by an increased seizure and ischemia susceptibility in K2P2-deleted mice (Heurteaux et al., 2004); moreover, the neuroprotection typically provided by PUFAs and lysophospholipids after seizure or ischemia was abrogated in K2P2-knockout mice, implicating lipid activation of the channel in this form of neuroprotection (Heurteaux et al., 2004).

In sum, K2P2, K2P4, and K2P10 represent a subfamily of channels with unique structural and functional features, some shared and some distinct, that underlie their characteristic polymodal regulation. These broad regulatory properties, along with expression throughout the central and peripheral nervous system, allow these specific K2P channels to serve in various physiological and pharmacological processes. Most notably, they act as a “tunable” excitability brake in peripheral and central neurons, where they contribute to neuroprotection and modulate the effects of sensory inputs. Surprisingly, K2P2 and K2P10 are “off-target” substrates for clinically relevant pharmacological agents that nevertheless may mediate at least some of their salutary actions (e.g., effects of anesthetics or antidepressant drugs). It remains to be seen if any of these varied roles can be exploited with specific compounds in novel ways for therapeutic advantage (e.g., see Vivier et al., 2017).

TASK Family

The TASK (TWIK-related acid-sensitive K+ channel) family includes three subunits. The two functional subunits, K2P3 (TASK-1) and K2P9 (TASK-3), are widely expressed in the nervous system (Fig. 2A) and a number of other tissues (Aller & Wisden, 2008; Medhurst et al., 2001; Talley et al., 2001), where they produce K+-selective background currents that are inhibited by extracellular acidification; these channels are also targets for inhibition by Gαq-coupled receptors, and for activation by inhalational anesthetics (Bayliss, Sirois, & Talley, 2003; Enyedi & Czirjak, 2010; Kim, 2005; Lesage & Barhanin, 2011). K2P15 (TASK-5) is a silent subunit that is differentially expressed in the brain, especially in auditory nuclei (Ashmole, Goodwin, & Stanfield, 2001; Karschin et al., 2001; Kim & Gnatenco, 2001); we will not consider it further here.

Tandem Pore Domain Potassium ChannelsClick to view larger

Figure 2TASK channels: Distribution and modulation. A. In situ hybridization analysis of K2P3 and K2P9 expression in rat brain; note the differential but overlapping pattern of expression (adapted with permission from Talley et al., 2003). B. Single-channel TASK-like currents from cerebellar granule cells, which express both K2P3 and K2P9, display properties similar to recombinant linked K2P3:K2P9 channels expressed in COS-7 cells. Note the voltage-dependent gating and the prominent inward rectification in the single-channel records of native and recombinant channels (adapted from Kang, Han, et al., 2003, with permission from John Wiley & Sons). C. Weak outward rectification of pH- and anesthetic-sensitive whole cell currents from recombinant K2P3:K2P9 channels expressed in HEK293 cells; the inset provides a cartoon of the concatenated TASK-1/TASK-3 construct (adapted from Berg et al., 2004). D–F. As observed with recombinant K2P3:K2P9 channels, native TASK-like currents in hypoglossal motoneurons are jointly regulated by extracellular pH, inhalational anesthetics, and neurotransmitters (5-HT, serotonin); the weakly rectifying whole cell I–V relationships represent the pH-sensitive components of anesthetic-activated (D; adapted from Sirois et al., 2000) and 5-HT inhibited current (E; adapted from Talley et al., 2000, with permission from Elsevier), and the halothane-sensitive component of 5-HT inhibited current (F; adapted from Sirois et al., 2002, with permission from John Wiley & Sons). These TASK-like current components were eliminated in motoneurons from K2P3:K2P9 (TASK) knockout mice (Lazarenko, Willcox, et al., 2010).

For K2P3 and K2P9, inward rectification of single-channel conductance coupled with modest voltage- and time-dependence of channel-open probability yields whole cell pH- and anesthetic-sensitive I–V relationships that are reasonably well fitted in physiological solutions by the GHK equation (Kim, 2005; Renigunta et al., 2015) (Fig. 2B, 2C). The channel kinetics of K2P3 and K2P9 are similar, but single-channel conductance is larger and divalent-sensitive for K2P9 (36 pS vs. 100 pS, in 1 mM and 0 mM divalents), and smaller and divalent-insensitive for K2P3 (~14 pS) (Kim, 2005). For both, proton inhibition requires a histidine residue near the first pore selectivity filter (His-98); despite this shared titratable residue, the two channels show notably different pH sensitivity that is conferred by additional divergent nearby residues (pKa for K2P3 ~7.4; for K2P9 ~6.7) (Kim, Bang, & Kim, 2000; Lopes, Zilberberg, & Goldstein, 2001; Rajan et al., 2000).

Surface expression of K2P3 and K2P9 is facilitated by protein–protein interactions, including by C-terminal binding to 14-3-3 proteins. This binding is dependent on PKA- or RSK2-mediated phosphorylation of the channel, and leads to release of β-coatamer binding to an N-terminal endoplasmic reticulum (ER) retention signal (Kilisch, Lytovchenko, Schwappach, Renigunta, & Daut, 2015; O’Kelly, Butler, Zilberberg, & Goldstein, 2002; Rajan et al., 2002; Renigunta et al., 2006; Zuzarte et al., 2009).

Structural diversity for K2P3 and K2P9 arises from heteromeric channel assembly; there are no splice variants produced from their cognate two-exon genes. The expression patterns for K2P3 and K2P9 are widespread, but distinct (Aller & Wisden, 2008; Medhurst et al., 2001; Talley et al., 2001); in some cell types, there is expression of only one subunit (e.g., K2P9 in striatal cholinergic cells) (Berg & Bayliss, 2007; Talley et al., 2001), whereas overlapping expression of both subunits is observed in other cell groups (e.g., cerebellar granule neurons, motor and sensory neurons, carotid body glomus cells, adrenocortical cells) (Aller & Wisden, 2008; Czirjak & Enyedi, 2002; Czirjak, Fischer, Spat, Lesage, & Enyedi, 2000; Davies et al., 2008; Heitzmann et al., 2008; Kim, Cavanaugh, Kim, & Carroll, 2009; Medhurst et al., 2001; Penton et al., 2012; Talley et al., 2001). As might be expected from this distribution, K2P3 and K2P9 subunits form homodimeric and heterodimeric channels, which have been identified in a number of native contexts based on conformation-specific constellations of single-channel and pharmacological properties (Berg et al., 2004; Kang, Han, et al., 2004; Kim et al., 2009) (Fig. 2B). In addition, as mentioned previously, heterodimers of K2P3 or K2P9 with K2P1 have also been observed in cerebellar granule neurons, where they were silenced by sumoylation of the K2P1 subunit (Plant et al., 2012).

A major regulatory feature, described in early studies of K2P3 and K2P9 channels, involves their inhibition downstream of Gαq-coupled receptors (Czirjak, Petheo, Spat, & Enyedi, 2001; Millar et al., 2000; Talley, Lei, Sirois, & Bayliss, 2000). Indeed, this receptor-mediated neuronal “leak” K+ current inhibition was well known in neurons (Nicoll, 1988; Nicoll et al., 1990), and it now appears that these channels are a likely substrate for that current in various cell types (Enyedi & Czirjak, 2010). A number of signaling pathways have been described for this receptor-mediated mechanism, including direct inhibition by the activated Gαq subunit (Chen et al., 2006) and either PIP2 depletion (Lopes et al., 2005) or diacylyglycerol (DAG) production (Lindner, Leitner, Halaszovich, Hammond, & Oliver, 2011; Wilke et al., 2014) that would occur via Gαq-stimulated PLC activity (Czirjak et al., 2001; Wilke et al., 2014); the relative contributions of these pathways may be context-dependent (Mathie, 2007). Gαq-mediated channel modulation may be opposed by PKC phosphorylation (Veale et al., 2007), but there is little evidence for other effects of channel phosphorylation, or for modulation of K2P3 or K2P9 by Gαs- or Gαi-coupled receptors. As with K2P2 channels, a proximal C-terminal region is also required for receptor-mediated inhibition of K2P3 and K2P9 (Talley & Bayliss, 2002).

Interestingly, this proximal C-terminal region is also required for activation of these channels by inhalational anesthetics (Patel et al., 1999; Talley & Bayliss, 2002), another well-known form of regulation for K2P3 and K2P9; residues critical for anesthetic activation have also been identified in regions outside from the proximal C terminus (Andres-Enguix et al., 2007). It remains to be determined whether these functionally important channel regions represent true binding sites or domains that transduce gating information from remote binding sites. Among these different forms of regulation, channel inhibition appears to prevail since anesthetic activation is completely abrogated in channels simultaneously inhibited by either extracellular acidification or Gαq receptor signaling (Meuth et al., 2003; Sirois, Lynch, & Bayliss, 2002; Talley & Bayliss, 2002); the joint pH-, anesthetic-, and transmitter-sensitive components of native motoneuronal currents present with TASK-like I–V characteristics (Fig. 2D-F), and they are eliminated in K2P3:K2P9 double knockout mice (Berg et al., 2004; Lazarenko, Willcox, et al., 2010; Sirois, Lei, Talley, Lynch, & Bayliss, 2000; Sirois et al., 2002).

K2P3 and K2P9 are also inhibited by hypoxia (low oxygen tension), an effect that was initially noted in presumed native correlates of these channels recorded in oxygen-sensitive glomus cells of the carotid body (Buckler, 1997, 2015; Buckler, Williams, & Honore, 2000); these channels were also implicated in O2-mediated contraction of pulmonary arterial smooth muscle cells (Gurney et al., 2003; Olschewski et al., 2006), and mutations in K2P3 are associated with pulmonary hypertension in humans (Lambert et al., 2018). The native O2-sensitive channels in peripheral arterial chemoreceptors were subsequently identified definitively as K2P3 and K2P9, first based on detailed comparisons to single-channel properties of the cloned channels (Buckler et al., 2000; Kim et al., 2009), and then by using knockout mice (Turner & Buckler, 2013). These analyses concluded that the predominant native form of the O2-sensitive channel in carotid body glomus cells is the K2P3:K2P9 heterodimer (Kim et al., 2009; Turner & Buckler, 2013). On the other hand, deletion of K2P3 and K2P9 had little to no effect on pulmonary arterial smooth muscle cells, and it did not disrupt hypoxic vasoconstriction (Manoury, Lamalle, Oliveira, Reid, & Gurney, 2011; Murtaza et al., 2017); this may reflect some species-dependent differences in K2P channel expression that are peculiar to mice (Manoury et al., 2011; Murtaza et al., 2017). The mechanism for channel inhibition by hypoxia remains unsettled, but it is likely to be indirect and mediated by metabolic changes associated with reduced O2 levels in glomus cells (Buckler, 2015; Kim, 2013).

With respect to physiological roles for K2P3 and K2P9 channels, their demonstrated pH and O2 sensitivity, together with expression in carotid body and brainstem regions associated with respiratory control, suggested that they could be involved in chemoreceptor-mediated stimulation of breathing (i.e., by hypoxia and CO2-induced acidosis). However, this is not supported by data from knockout mice. In the case of carotid body chemoreceptors, hypoxia-stimulated breathing was normal despite reduced K2P3 and K2P9 channel activity (Ortega-Saenz et al., 2010; Trapp, Aller, Wisden, & Gourine, 2008); thus, although the O2-sensitive K2P3:K2P9 channels are expressed in glomus cells (Kim et al., 2009; Turner & Buckler, 2013), compensatory changes were apparent in these global knockouts, and multiple or redundant mechanisms probably contribute to carotid body stimulation of breathing (Buckler, 2015). Notably, pharmacological blockers of K2P3 and K2P9 can acutely stimulate breathing in wild-type mice (e.g., PK-THPP, A1899), and the respiratory stimulant doxapram inhibits these channels (Cotten, 2013; Cotten, Keshavaprasad, Laster, Eger, & Yost, 2006). There was also no effect of K2P3 and K2P9 deletion on CO2-induced stimulation of breathing, despite widespread expression of these pH-sensitive channels in brainstem respiratory neurons (Bayliss, Barhanin, Gestreau, & Guyenet, 2015; Bayliss, Talley, Sirois, & Lei, 2001; Mulkey et al., 2007). In the specific case of respiratory chemoreceptors located in the brainstem retrotrapezoid nucleus, the pH-sensitive mechanisms involve other channels (e.g., K2P5, see TALK Family, below) (Bayliss et al., 2015; Gestreau et al., 2010; Kumar et al., 2015; Wang et al., 2013). Thus, the neurobiological consequences of the pH and O2 sensitivity of these channels, K2P3 and K2P5, remain to be clarified.

Physiological data from mice deleted for K2P3 and/or K2P9 have revealed prominent roles in regulation of activity, sleep-wake patterning, and responses to anesthetics. Specifically, K2P9-knockout mice have markedly elevated nocturnal activity and fragmented rapid-eye-movement (REM) sleep, effects that are largely reproduced by a K2P9 blocker compound (Coburn et al., 2012; Pang et al., 2009); mice deleted for K2P3 and K2P9 are less sensitive to sedating, hypnotic, and immobilizing effects of inhaled anesthetics (Lazarenko, Willcox, et al., 2010; Linden et al., 2006; Linden et al., 2007). The precise mechanisms for these effects remains unclear. For activity and sleep regulation, this may reflect particularly high expression levels and state-dependent modulation in various aminergic neurons of the reticular activating system (e.g., noradrenergic locus coeruleus, serotonergic raphe, histaminergic tuberomammillary, cholinergic basal forebrain nuclei) (Karschin et al., 2001; Marinc, Preisig-Muller, Pruss, Derst, & Veh, 2011; Sirois et al., 2000; Steinberg, Wafford, Brickley, Franks, & Wisden, 2015; Talley et al., 2001; Vu, Du, Bayliss, & Horner, 2015; Washburn, Sirois, Talley, Guyenet, & Bayliss, 2002). In addition, Gαq receptor inhibition of K2P3 and K2P9, and the accompanying membrane depolarization, is a major mechanism for a state-dependent switch from sleep-related burst firing to wake-related tonic firing in thalamocortical relay neurons (Bista et al., 2015; Bista et al., 2012). Conversely, activation of K2P3 and K2P9 channels in these same aminergic and thalamocortical cell groups may contribute to the sedating and hypnotic effects of inhalational anesthetics (Budde et al., 2008; Meuth et al., 2003; Sirois et al., 2000; Washburn et al., 2002). Immobilizing anesthetic actions mediated by K2P3 and K2P9 probably arise from anesthetic-induced hyperpolarization in motoneurons, since deletion of K2P3 and K2P9 from cholinergic neurons recapitulates the decreased anesthetic sensitivity of global knockout mice (Lazarenko, Willcox, et al., 2010). These channels also contribute to the neuroprotection in mouse models of stroke (Meuth et al., 2009), including the neuroprotective effects of inhalational anesthetics (C. Yao et al., 2017).

As with other K2P channels, K2P3 and K2P9 are expressed in peripheral sensory neurons where they can act as a modifiable brake on cell excitability. These channels, along with K2P18, are inhibited by a number of pungent agents (e.g., hydroxy-α-sanshool, from Szechuan peppercorns; piperines, from black peppercorns), providing a TRP (transient receptor potential) channel-independent mechanism for detecting chemicals that yield a distinct sensation (i.e., tingling paresthesia, numbing) (Bautista et al., 2008; Beltran et al., 2017). In addition, K2P9 is preferentially expressed at high levels in cold- and menthol-sensitive TRPM8-containing sensory neurons, and cold hypersensitivity is observed in mice deleted for K2P9 (Morenilla-Palao et al., 2014). Outside the nervous system, K2P3 and K2P9 are expressed in the heart, where they can contribute to action potential repolarization (Decher, Kiper, Rolfes, Schulze-Bahr, & Rinne, 2015; Rinne et al., 2015). K2P3 and K2P9 are also expressed in the mouse adrenal cortex, with K2P9 selectively localized to the zona glomerulosa, and expressed in mitochondria (Davies et al., 2008; Guagliardo et al., 2012; J. Yao et al., 2017). Genetic deletion of K2P3 disrupts zonation in female mice (Heitzmann et al., 2008); in male mice, deletion of K2P3 and/or K2P9 leads to a continuum of aldosteronism with elevated blood pressure (Davies et al., 2008; Guagliardo et al., 2012; Heitzmann et al., 2008; Penton et al., 2012). Finally, a role for these channels has been suggested for metabolic functions, such as dampening of lipolysis and thermogenesis in adipocytes (Chen et al., 2017; Pisani et al., 2016) and control of glucagon and insulin secretion from pancreatic α and β cells (Dadi, Luo, Vierra, & Jacobson, 2015; Dadi, Vierra, & Jacobson, 2014).

Although mice deleted for K2P3 and K2P9 have relatively minor impairments in the absence of physiological challenge (Lazarenko, Willcox, et al., 2010; Linden et al., 2006; Linden et al., 2007), the channels have been implicated in normal neuronal development. For example, in the cerebellum and hippocampus, K2P9 may contribute to apoptosis and cell proliferation, respectively. Moreover, invalidation of these channels affects leak conductance and firing properties in these and other neurons (Aller et al., 2005; Brickley et al., 2007; Gonzalez et al., 2009). Missense mutations of KCNK9 that strongly reduce K2P9 currents lead to a mental retardation dysmorphism (Birk-Barel) syndrome in human patients (Barel et al., 2008; Veale, Hassan, Walsh, Al-Moubarak, & Mathie, 2014). Interestingly, gene deletion of a GABA receptor subunit that typically underlies a constitutive outward current in cerebellar cells leads to a compensatory upregulation of K2P3 and K2P9, seemingly to preserve normal neuronal excitability (Brickley, Revilla, Cull-Candy, Wisden, & Farrant, 2001). Thus, as principal determinants of membrane potential and excitability in many neurons, there must be substantial developmental pressure for homeostatic compensatory mechanisms to protect neurons from K2P channel dysfunction.

In sum, K2P3 and K2P9 are expressed widely throughout the nervous system, with particularly prominent expression in brainstem aminergic neurons and motoneurons; they are capable of forming homomeric and heteromeric channels that generate background K+ currents, which are renowned for their inhibition by protons, Gαq-coupled receptors and hypoxia, and for their activation by inhalational anesthetics. As such, K2P3 and K2P9 account for multiple instances of receptor-mediated neuromodulation involving “leak” K+ channel inhibition, effects that may be particularly important for regulating arousal state-dependent activity and sleep patterning. The physiological relevance of channel-intrinsic pH sensitivity and indirect hypoxia sensitivity remains unclear, but the latter is likely to be involved in breathing regulation by carotid body oxygen chemoreceptors. Activation of K2P3 and K2P9 by inhalational anesthetics contributes to multiple clinically relevant actions (sedation, hypnosis, immobilization, neuroprotection); in sensory neurons, K2P9 depresses cold sensitivity, and K2P3 and K2P9 are inhibited by pungent agents that evoke tingling sensations. During neuronal development, K2P3 and/or K2P9 can homeostatically regulate cell excitability or influence cell proliferation and apoptosis; loss-of-function mutations in K2P9 are associated with the Birk-Barel syndrome. There has been some success in developing compounds specific for K2P3 and K2P9; activators and inhibitors targeting these channels will provide useful complements to genetic studies for experimental analysis of their physiological function, with potential therapeutic utility.

TALK Family

The TALK (TWIK-related alkaline pH-activated K+ channel) family comprises three subunits: K2P5 (TASK-2), K2P16 (TALK-1) and K2P17 (TALK-2). The members of this K2P subgroup are pH-dependent over a broad range and, as suggested by their name, display increasing activity as extracellular pH becomes progressively alkalized (Lesage & Barhanin, 2011). In contrast to other pH-sensitive K2P channels, for which histidine residues located in either the M1P1 loop or the pore are implicated (TREK and TASK families) (Lesage & Barhanin, 2011; Sepulveda et al., 2015), the basis for pH sensitivity in TALK family channels appears to involve positively charged residues in the P2M4 loop (e.g., Arg224 in K2P5, Lys242 in K2P17) (Niemeyer et al., 2007; Sepulveda et al., 2015). The channels are K+-selective, active at negative membrane potentials, and they activate with some time-dependence upon depolarization to yield a modest, outwardly rectifying I–V relationship (Duprat, Girard, Jarretou, & Lazdunski, 2005; Girard et al., 2001; Han, Kang, & Kim, 2003; Kang & Kim, 2004; Reyes et al., 1998) that contrasts with the inward rectification observed for each of these K2P subunits at the single-channel level (Han et al., 2003; Kang & Kim, 2004). Notably, this subgroup of channels can be strongly activated by nitric oxide (NO) and specific reactive oxygen species (ROS) (Duprat et al., 2005; Gestreau et al., 2010); they also may be receptor modulated, since K2P5 can be inhibited by G protein βγ subunits (Anazco et al., 2013).

In general, this subgroup of K2P channels is thought to be most highly expressed in peripheral tissues (e.g., pancreas, kidney, cochlea) (Lesage & Barhanin, 2011), where the channels have been found to play critical roles in secretory processes. For example, deletion of K2P5 in mice disrupts HCO3- reabsorption from the kidney to precipitate a metabolic acidosis (Warth et al., 2004); loss of K2P5 also interferes with K+ recycling by cochlear cells, resulting in progressive deafness (Cazals et al., 2015); and genetic ablation of K2P16 depolarizes pancreatic β cells to increase glucose-stimulated insulin secretion (Vierra et al., 2015). Since expression of this K2P subgroup has been considered to be predominantly peripheral (Lesage & Barhanin, 2011), possible roles for these channels in neuronal function remain largely unexplored—with the following notable exception.

A highly restricted brainstem expression of K2P5 was uncovered by using β-galactosidase staining in a mouse expressing LacZ from a gene trap embedded in the Kcnk5 locus (Gestreau et al., 2010). Among the brainstem cell groups found to be positive for expression of this pH-sensitive K2P5 channel was the so-called retrotrapezoid nucleus (RTN), which contains a set of neurons that are responsible for sensing changes in CO2/H+ for the purpose of regulating breathing (Gestreau et al., 2010; Wang et al., 2013)—a homeostatic reflex that rapidly regulates CO2 levels and acid–base balance (Bayliss et al., 2015; Guyenet & Bayliss, 2015). Accordingly, genetic deletion of K2P5 in mice eliminated pH sensitivity in a subpopulation of RTN neurons (Wang et al., 2013), and it strongly blunted CO2-induced stimulation of breathing (Gestreau et al., 2010); a second receptor-mediated inhibition of an unidentified background K+ channel accounted for much of the residual neuronal pH sensitivity and breathing stimulation by CO2 (Guyenet & Bayliss, 2015; Kumar et al., 2015). Interestingly, then, via expression in these brainstem RTN neurons and in the kidney, K2P5 contributes to both acute and chronic mechanisms of acid-base regulation (Bayliss et al., 2015; Warth et al., 2004). A separate effect of K2P5 deletion on the respiratory response to hypoxia was also observed, prompting the interesting speculation that this might reflect a ROS-mediated activation of K2P5 (Gestreau et al., 2010); this latter hypothesis remains untested.

In sum, the TALK family of K2P channels generates outwardly rectifying “leak” K+ currents that are strongly activated by alkalization over a broad pH range, and by NO or ROS. Although these subunits are typically considered to be important in peripheral organs, there may be discrete sites of expression for this subgroup within the nervous system that could mediate important physiological functions; this is the case for K2P5, which provides a molecular substrate for pH-dependent regulation of breathing by virtue of its expression in RTN neurons. Similar discoveries of other neuronal functions may yet be made for K2P16 and K2P17.

THIK Family

The THIK (Tandem pore domain halothane-inhibited K+ channel) family includes K2P12 (THIK-2) and K2P13 (THIK-1), both of which show differential, but overlapping, expression in the brain (Rajan et al., 2001). Initial recordings from these subunits revealed K+ selective currents and GHK-type rectification for K2P13 (Rajan et al., 2001); unlike other K2P channels mentioned previously, the K2P13 channel currents are inhibited, rather than activated, by the inhalational anesthetic halothane (Rajan et al., 2001). On the other hand, K2P12 failed to generate any currents, either when expressed alone or together with K2P13 in various heterologous expression systems (Blin et al., 2014; Chatelain et al., 2013; Rajan et al., 2001; Renigunta et al., 2014). However, more recent work indicates that K2P12 can be trafficked to the cell surface to generate halothane-inhibited K+ currents, similar to those mediated by K2P13, if strong N-terminal ER retention signals are disrupted by mutation or masked by co-expressed K2P13 (Blin et al., 2014; Chatelain et al., 2013; Renigunta et al., 2014). The shared properties of whole cell currents from homomeric K2P12 and K2P13 channels are reflected in similar current properties obtained from the corresponding heteromeric K2P12:K2P13 channels. Nonetheless, as observed for other K2P heterodimers, the single-channel conductance of the K2P12:K2P13 heterodimers (~3.5 pS) could be distinguished from that of either of the homomeric channels (K2P13: ~5 pS; K2P12: ~2.5 pS), despite the short, flickery openings for these very small conductance K2P channels (Blin et al., 2014; Kang, Hogan, & Kim, 2014).

There has been relatively little information regarding native correlates or physiological functions for K2P12- and/or K2P13-containing channels. In microglia, ATP and P2Y purinergic receptors activate a tonic background K+ current with pharmacological characteristics similar to K2P13 that is absent in Kcnk13 knockout mice (Madry et al., 2018). Interestingly, either pharmacological or genetic interference with K2P13 channel function reduced microglia surveillance and inflammatory cytyokine release, with an important role for tonic K2P13 activity in surveillance function and for ATP-stimulated channel activity in inflammasone activation (Madry et al., 2018).

The defining characteristic that inspired the common name for this group of K2P channels is their inhibition by inhalational anesthetics (Rajan et al., 2001). Accordingly, a native halothane-inhibited Purkinje cell current was attributed to K2P13, based on its expression in cerebellar Purkinje neurons (Bushell, Clarke, Mathie, & Robertson, 2002; Ishii, Nakajo, Yanagawa, & Kubo, 2010); interestingly, this Purkinje cell current and recombinant K2P13 were both found to be permeable to Cs+ and activated by G protein βγ subunits, suggesting an effector role downstream of GABAB receptor signaling in those neurons (Ishii et al., 2010). Respiratory chemoreceptor neurons also express K2P13 and a native halothane-inhibited “leak” K+ current (Lazarenko, Fortuna, et al., 2010); the excitatory influence of this K2P13-mediated modulation on these RTN neurons, which provide a major drive for breathing, may contribute to maintained respiration during general anesthesia, even as other motor systems are strongly suppressed (Lazarenko, Fortuna, et al., 2010). Likewise, a halothane-inhibited “leak” K+ current was also found to provide a direct excitation of sleep-active neurons of the ventrolateral preoptic nucleus (VLPO) (Moore et al., 2012); although not directly linked to K2P12 or K2P13, it was suggested that activation of those neurons via this mechanism might coopt this component of the physiological sleep network to facilitate the loss of consciousness associated with those anesthetic drugs (Moore et al., 2012).

A role for K2P13 in mediating a hypoxia-sensitive K+ current in a subset of nitric oxide-synthase positive glossopharyngeal sensory neurons was suggested based on the demonstration that the neuronal hypoxia-sensitive current was occluded by halothane (Campanucci, Fearon, & Nurse, 2003), and that recombinant K2P13 was modestly inhibited by hypoxia after heterologous expression in HEK293 cells (Campanucci et al., 2003; Fearon et al., 2006; but see Kang et al., 2014). A small conductance halothane-inhibited channel with short, flickery openings reminiscent of K2P13 was observed in trigeminal ganglion neurons (Kang et al., 2014); like recombinant K2P13, this native channel was activated by arachidonic acid and strongly inhibited by cold (Kang et al., 2014), perhaps contributing to temperature-sensitive K+ channels previously recorded in cold-activated sensory neurons (Madrid, de la Pena, Donovan-Rodriguez, Belmonte, & Viana, 2009; Viana, de la Pena, & Belmonte, 2002).

In sum, K2P12 and K2P13 can generate weakly rectifying background K+ currents in physiological conditions; these K2P channels are notable for their very small unitary conductance, flickery activity, and inhibition by halothane and other inhaled anesthetics. By masking a powerful intracellular retention signal on K2P12, the related K2P13 may permit surface expression of heterodimeric K2P12:K2P13 channels at sites where the subunits are co-expressed. At present, only circumstantial evidence attributes native currents to these channels, with possible roles proposed in mediating specific effects of anesthetics or contributing to cold sensation.

TRESK Family

The TRESK (TWIK-related spinal cord K+ channel) family includes a single member K2P18 (TRESK), which obtained its moniker because it was originally cloned from spinal cord cDNA and because initial observations suggested a predominantly spinal expression pattern (Sano et al., 2003). However, this selective expression has not been borne out in subsequent quantitative analyses, which find a more widespread localization pattern and particularly high levels of K2P18 transcripts in sensory ganglia (Bautista et al., 2008; Cadaveira-Mosquera et al., 2012; Czirjak, Toth, & Enyedi, 2004; Dobler et al., 2007; Kang & Kim, 2006; Keshavaprasad et al., 2005). The major structural distinctions of K2P18, by comparison to other K2P channels, are an especially long M2M3 intracellular loop domain and short C-terminal region; these characteristics are preserved among species orthologues, which otherwise show particularly low primary sequence conservation (Kang, Mariash, & Kim, 2004; Sano et al., 2003). In heterologous expression systems, K2P18 channels generate a nearly instantaneous, weakly rectifying K+-selective whole cell current (Kang, Mariash, et al., 2004; Sano et al., 2003); the underlying channels exhibit an asymmetrical gating behavior, with low conductance openings (<20 pS) that are well resolved at depolarized potentials but that exhibited short bursts of highly flickery activity at negative membrane potentials (Czirjak et al., 2004; Kang, Mariash, et al., 2004).

The major regulatory features identified for K2P18 involve actions at the extended intracellular M2M3 loop unique to this channel. In particular, K2P18 is activated by Gαq-coupled receptor signaling via de-phosphorylation of a regulatory cluster of serine residues in this loop by calcineurin, a calcium-dependent phosphatase (Czirjak & Enyedi, 2010; Czirjak et al., 2004); basal inhibitory phosphorylation at those sites may be mediated by microtubule affinity-regulating kinases (MARKs) (Braun, Nemcsics, Enyedi, & Czirjak, 2011). In addition, the M2M3 loop coordinates various additional protein interactions (e.g., with 14-3-3 proteins) that can modulate phosphorylation-based regulation of the channel (Czirjak, Vuity, & Enyedi, 2008). Modest extracellular pH sensitivity was observed for mouse K2P18 and attributed to a pore-adjacent histidine (Kang, Mariash, et al., 2004; Keshavaprasad et al., 2005); the absence of that residue appears to account for the lack of pH sensitivity in the human K2P18 orthologue (Dobler et al., 2007). Although K2P18 is expressed in sensory ganglia and activated by inhalational anesthetics (Keshavaprasad et al., 2005; Liu, Au, Zou, Cotten, & Yost, 2004), gene deletion had negligible effects on anesthetic sensitivity in mice (Chae et al., 2010).

The high levels of K2P18 expression in sensory neurons suggested a role in regulating their excitability and associated physiological functions. Indeed, K2P18 accounts for a substantial fraction of background K+ current in sensory neurons of dorsal root and trigeminal ganglia, and interfering with K2P18 channel expression or function increases sensory neuron excitability (Dobler et al., 2007). For example, mechanical hypersensitivity was evoked by reduced expression of K2P18 in DRG neurons, produced either by siRNA treatment or following nerve injury in a neuropathic pain model (Tulleuda et al., 2011; Zhou, Yang, Zhong, & Wang, 2013). The pungent ingredient in Szechuan peppers, α-hydroxy sanshool, causes a tingling sensation in the mouth and evokes aversive responses in behavioral experiments; this was attributed to inhibition by sanshool of K2P18 in sensory neurons (Bautista et al., 2008), although contributions from various additional K2P and other channels are also likely (e.g., K2P3, K2P9, TRPV1, NaV1.7) (Bautista et al., 2008; Koo et al., 2007; Riera et al., 2009; Tsunozaki et al., 2013).

A specific KCNK18 frameshift mutation (F139WfsX24) was discovered in patients experiencing migraine with aura; the truncated protein product acts as a dominant negative in trigeminal ganglion neurons, and increased excitability due to loss of K2P18 function in pain-associated trigeminal neurons is a plausible mechanism for the debilitating migraine headaches (Lafreniere et al., 2010). Notably, all the patients carrying this mutation also reported aura symptoms, suggesting that disrupting K2P18 could contribute to that aberrant cortical behavior as well, and implying a normal role for K2P18 in limiting excitability of central neurons. It is important to note that although this F139WfsX24 variant was clearly linked to migraine with aura, other loss-of-function mutations in K2P18 did not show any genetic association with migraine (Andres-Enguix et al., 2012), suggesting a more complex and multifactorial etiology for K2P18 contributions to this disorder.

In sum, K2P18 stands apart from the other K2P channels. It displays “leak” type whole cell K+ currents typical of the family that nonetheless belie unusual asymmetrical single-channel properties. It has an unusually short C-terminal region and long intracellular loop domain, the latter serving as a regulatory site for receptor- and calcineurin-mediated channel activation. Expression of K2P18 is particularly high in sensory ganglia, where it normally contributes to dampening neuronal excitability; decreased expression after nerve injury may underlie the sensory neuron hyperexcitability associated with neuropathic pain, and dominant negative mutations of the channel are implicated in a subset of patients who experience painful migraine, with aura.

Summary

The K2P channel family presents structural features and functional properties that are distinctly different from those of other K+ channels. K2P channels assemble as homo- or heterodimers, bringing together the two pore-domains from each subunit to form a pseudotetrameric K+-selective pore. Further unique features include a large extracellular cap structure that overlies a pair of electronegative pathways for K+ ions to reach the selectivity filter, and a prominent hydrophobic fenestration that links the membrane bilayer to the inner channel vestibule. Characteristic weakly rectifying K2P currents are present over wide voltage ranges, including at resting membrane potentials (i.e., “leak” currents), but these macroscopic current profiles are typically the product of underlying single-channel rectification and modest voltage-dependent gating. The channel gate is localized to the selectivity filter, rather than at an intracellular bundle crossing, and gating is dynamically regulated by convergent effects of multiple channel-specific modulators, in many cases via actions on a proximal C-terminal helix region.

Modulatory mechanisms peculiar to each channel subtype allow adjustment of membrane potential and electroresponsive properties in K2P-expressing cells by a variety of physicochemical factors, neurochemicals, and clinically relevant drugs. The TWIK family of channels exemplifies multiple novel regulatory features, including reversible SUMOlyation, rapid endocytic recycling, pore de-wetting, and dynamic ion selectivity. TREK channel variants, with distinct unitary properties arising from differential splicing and alternative translation initiation, are polymodal signal integrators: channel activity is regulated by an incredibly diverse set of factors (e.g., stretch, pH, temperature, lipid and protein interactions, inhalational anesthetics, antidepressants, and by up- and down-modulation by GPCRs). TASK channels are activated by inhalational anesthetics and inhibited by GαqPCRs, low oxygen tension and protons; they may contribute to hypoxia-stimulated breathing, sleep patterning, arousal state, and anesthetic actions. TALK channels are activated by alkaline pH, nitric oxide, and reactive oxygen species; they are expressed most prominently outside the central nervous system, but TASK-2 contributes to CO2-regulated breathing by the brainstem. In contradistinction to other K2P channels, THIK channels are inhibited rather than activated by inhalational anesthetics; heterodimerization with K2P13 allows surface trafficking to unsilence K2P12. The single TRESK channel subunit is the most diverse, presenting an extended cytoplasmic loop domain that mediates dynamic, phosphorylation-dependent channel modulation; mutations in K2P18 are associated with migraines, with aura.

In sum, K2P channels underlie background K+ currents that provide a tunable brake on cellular excitability. These channels contribute particularly prominently to sensory neuron function and to regulation of brain state, and, surprisingly, they have been associated with clinical actions of various well-known drugs (e.g., anesthetics and antidepressants). There are currently few subunit-selective drugs targeting individual types of K2P channels, but such compounds may find use in treating dysfunctions of the myriad systems in which these channels are now appearing to play a key role.

References

Acosta, C., Djouhri, L., Watkins, R., Berry, C., Bromage, K., & Lawson, S. N. (2014). TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. Journal of Neuroscience, 34(4), 1494–1509. doi:10.1523/JNEUROSCI.4528-13.2014Find this resource:

Aller, M. I., Veale, E. L., Linden, A. M., Sandu, C., Schwaninger, M., Evans, L. J., … Brickley, S. G. (2005). Modifying the subunit composition of TASK channels alters the modulation of a leak conductance in cerebellar granule neurons. Journal of Neuroscience, 25(49), 11455–11467. doi:10.1523/JNEUROSCI.3153-05.2005Find this resource:

Aller, M. I., & Wisden, W. (2008). Changes in expression of some two-pore domain potassium channel genes (KCNK) in selected brain regions of developing mice. Neuroscience, 151(4), 1154–1172. doi:10.1016/j.neuroscience.2007.12.011Find this resource:

Alloui, A., Zimmermann, K., Mamet, J., Duprat, F., Noel, J., Chemin, J., … Lazdunski, M. (2006). TREK-1, a K+ channel involved in polymodal pain perception. EMBO Journal, 25(11), 2368–2376. doi:10.1038/sj.emboj.7601116Find this resource:

Anazco, C., Pena-Munzenmayer, G., Araya, C., Cid, L. P., Sepulveda, F. V., & Niemeyer, M. I. (2013). G protein modulation of K2P potassium channel TASK-2: A role of basic residues in the C terminus domain. Pflügers Archiv, 465(12), 1715–1726. doi:10.1007/s00424-013-1314-0Find this resource:

Andres-Enguix, I., Caley, A., Yustos, R., Schumacher, M. A., Spanu, P. D., Dickinson, R., … Franks, N. P. (2007). Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: Molecular cloning of an anesthetic-activated potassium channel from Lymnaea stagnalis. Journal of Biological Chemistry, 282(29), 20977–20990. doi:10.1074/jbc.M610692200Find this resource:

Andres-Enguix, I., Shang, L., Stansfeld, P. J., Morahan, J. M., Sansom, M. S., Lafreniere, R. G., … Tucker, S. J. (2012). Functional analysis of missense variants in the TRESK (KCNK18) K channel. Scientific Reports, 2, 237. doi:10.1038/srep00237Find this resource:

Aryal, P., Abd-Wahab, F., Bucci, G., Sansom, M. S., & Tucker, S. J. (2014). A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel. Nature Communications, 5, 4377. doi:10.1038/ncomms5377Find this resource:

Ashmole, I., Goodwin, P. A., & Stanfield, P. R. (2001). TASK-5, a novel member of the tandem pore K+ channel family. Pflügers Archiv, 442(6), 828–833.Find this resource:

Bagriantsev, S. N., Clark, K. A., & Minor, D. L., Jr. (2012). Metabolic and thermal stimuli control K(2P)2.1 (TREK-1) through modular sensory and gating domains. EMBO Journal, 31(15), 3297–3308. doi:10.1038/emboj.2012.171Find this resource:

Bagriantsev, S. N., Peyronnet, R., Clark, K. A., Honore, E., & Minor, D. L., Jr. (2011). Multiple modalities converge on a common gate to control K2P channel function. EMBO Journal, 30(17), 3594–3606. doi:10.1038/emboj.2011.230Find this resource:

Barel, O., Shalev, S. A., Ofir, R., Cohen, A., Zlotogora, J., Shorer, Z., … Birk, O. S. (2008). Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. American Journal of Human Genetics, 83(2), 193–199. doi:10.1016/j.ajhg.2008.07.010Find this resource:

Bautista, D. M., Sigal, Y. M., Milstein, A. D., Garrison, J. L., Zorn, J. A., Tsuruda, P. R., … Julius, D. (2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neuroscience, 11(7), 772–779. doi:10.1038/nn.2143Find this resource:

Bayliss, D. A., Barhanin, J., Gestreau, C., & Guyenet, P. G. (2015). The role of pH-sensitive TASK channels in central respiratory chemoreception. Pflügers Archiv, 467(5), 917–929. doi:10.1007/s00424-014-1633-9Find this resource:

Bayliss, D. A., Sirois, J. E., & Talley, E. M. (2003). The TASK family: Two-pore domain background K+ channels. Molecular Interventions, 3(4), 205–219. doi:10.1124/mi.3.4.205Find this resource:

Bayliss, D. A., Talley, E. M., Sirois, J. E., & Lei, Q. (2001). TASK-1 is a highly modulated pH-sensitive “leak” K(+) channel expressed in brainstem respiratory neurons. Respiration Physiology, 129(1–2), 159–174.Find this resource:

Beltran, L. R., Dawid, C., Beltran, M., Levermann, J., Titt, S., Thomas, S., … Hatt, H. (2017). The effect of pungent and tingling compounds from Piper nigrum L. on background K(+) currents. Frontiers in Pharmacology, 8, 408. doi:10.3389/fphar.2017.00408Find this resource:

Berg, A. P., & Bayliss, D. A. (2007). Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K+ current. Journal of Neurophysiology, 97(2), 1546–1552. doi:10.1152/jn.01090.2006Find this resource:

Berg, A. P., Talley, E. M., Manger, J. P., & Bayliss, D. A. (2004). Motoneurons express heteromeric TWIK-related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits. Journal of Neuroscience, 24(30), 6693–6702. doi:10.1523/JNEUROSCI.1408-04.2004Find this resource:

Berrier, C., Pozza, A., de Lacroix de Lavalette, A., Chardonnet, S., Mesneau, A., Jaxel, C., … Ghazi, A. (2013). The purified mechanosensitive channel TREK-1 is directly sensitive to membrane tension. Journal of Biological Chemistry, 288(38), 27307–27314. doi:10.1074/jbc.M113.478321Find this resource:

Bichet, D., Blin, S., Feliciangeli, S., Chatelain, F. C., Bobak, N., & Lesage, F. (2015). Silent but not dumb: How cellular trafficking and pore gating modulate expression of TWIK1 and THIK2. Pflügers Archiv, 467(5), 1121–1131. doi:10.1007/s00424-014-1631-yFind this resource:

Bista, P., Cerina, M., Ehling, P., Leist, M., Pape, H. C., Meuth, S. G., & Budde, T. (2015). The role of two-pore-domain background K(+) (K(2)p) channels in the thalamus. Pflügers Archiv, 467(5), 895–905. doi:10.1007/s00424-014-1632-xFind this resource:

Bista, P., Meuth, S. G., Kanyshkova, T., Cerina, M., Pawlowski, M., Ehling, P., … Budde, T. (2012). Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons. Pflügers Archiv, 463(1), 89–102. doi:10.1007/s00424-011-1056-9Find this resource:

Blin, S., Ben Soussia, I., Kim, E. J., Brau, F., Kang, D., Lesage, F., & Bichet, D. (2016). Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties. Proceedings of the National Academy of Sciences of the United States of America, 113(15), 4200–4205. doi:10.1073/pnas.1522748113Find this resource:

Blin, S., Chatelain, F. C., Feliciangeli, S., Kang, D., Lesage, F., & Bichet, D. (2014). Tandem pore domain halothane-inhibited K+ channel subunits THIK1 and THIK2 assemble and form active channels. Journal of Biological Chemistry, 289(41), 28202–28212. doi:10.1074/jbc.M114.600437Find this resource:

Braun, G., Nemcsics, B., Enyedi, P., & Czirjak, G. (2011). TRESK background K(+) channel is inhibited by PAR-1/MARK microtubule affinity-regulating kinases in Xenopus oocytes. PLoS One, 6(12), e28119. doi:10.1371/journal.pone.0028119Find this resource:

Brickley, S. G., Aller, M. I., Sandu, C., Veale, E. L., Alder, F. G., Sambi, H., … Wisden, W. (2007). TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. Journal of Neuroscience, 27(35), 9329–9340. doi:10.1523/JNEUROSCI.1427-07.2007Find this resource:

Brickley, S. G., Revilla, V., Cull-Candy, S. G., Wisden, W., & Farrant, M. (2001). Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature, 409(6816), 88–92. doi:10.1038/35051086Find this resource:

Brohawn, S. G., Campbell, E. B., & MacKinnon, R. (2013). Domain-swapped chain connectivity and gated membrane access in a Fab-mediated crystal of the human TRAAK K+ channel. Proceedings of the National Academy of Sciences of the United States of America, 110(6), 2129–2134. doi:10.1073/pnas.1218950110Find this resource:

Brohawn, S. G., Campbell, E. B., & MacKinnon, R. (2014). Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature, 516(7529), 126–130. doi:10.1038/nature14013Find this resource:

Brohawn, S. G., del Marmol, J., & MacKinnon, R. (2012). Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science, 335(6067), 436–441. doi:10.1126/science.1213808Find this resource:

Brohawn, S. G., Su, Z., & MacKinnon, R. (2014). Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proceedings of the National Academy of Sciences of the United States of America, 111(9), 3614–3619. doi:10.1073/pnas.1320768111Find this resource:

Buckler, K. J. (1997). A novel oxygen-sensitive potassium current in rat carotid body type I cells. Journal of Physiology, 498 (Pt 3), 649–662.Find this resource:

Buckler, K. J. (2015). TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing. Pflügers Archiv, 467(5), 1013–1025. doi:10.1007/s00424-015-1689-1Find this resource:

Buckler, K. J., Williams, B. A., & Honore, E. (2000). An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells. Journal of Physiology, 525 Pt 1, 135–142.Find this resource:

Budde, T., Coulon, P., Pawlowski, M., Meuth, P., Kanyshkova, T., Japes, A., … Pape, H. C. (2008). Reciprocal modulation of I (h) and I (TASK) in thalamocortical relay neurons by halothane. Pflügers Archiv, 456(6), 1061–1073. doi:10.1007/s00424-008-0482-9Find this resource:

Bushell, T., Clarke, C., Mathie, A., & Robertson, B. (2002). Pharmacological characterization of a non-inactivating outward current observed in mouse cerebellar Purkinje neurones. British Journal of Pharmacology, 135(3), 705–712. doi:10.1038/sj.bjp.0704518Find this resource:

Cadaveira-Mosquera, A., Perez, M., Reboreda, A., Rivas-Ramirez, P., Fernandez-Fernandez, D., & Lamas, J. A. (2012). Expression of K2P channels in sensory and motor neurons of the autonomic nervous system. Journal of Molecular Neuroscience, 48(1), 86–96. doi:10.1007/s12031-012-9780-yFind this resource:

Cain, S. M., Meadows, H. J., Dunlop, J., & Bushell, T. J. (2008). mGlu4 potentiation of K(2P)2.1 is dependent on C-terminal dephosphorylation. Molecular and Cellular Neuroscience, 37(1), 32–39. doi:10.1016/j.mcn.2007.08.009Find this resource:

Campanucci, V. A., Fearon, I. M., & Nurse, C. A. (2003). A novel O2-sensing mechanism in rat glossopharyngeal neurones mediated by a halothane-inhibitable background K+ conductance. Journal of Physiology, 548(Pt 3), 731–743. doi:10.1113/jphysiol.2002.035998Find this resource:

Cazals, Y., Bevengut, M., Zanella, S., Brocard, F., Barhanin, J., & Gestreau, C. (2015). KCNK5 channels mostly expressed in cochlear outer sulcus cells are indispensable for hearing. Nature Communications, 6, 8780. doi:10.1038/ncomms9780Find this resource:

Chae, Y. J., Zhang, J., Au, P., Sabbadini, M., Xie, G. X., & Yost, C. S. (2010). Discrete change in volatile anesthetic sensitivity in mice with inactivated tandem pore potassium ion channel TRESK. Anesthesiology, 113(6), 1326–1337. doi:10.1097/ALN.0b013e3181f90ca5Find this resource:

Chatelain, F. C., Bichet, D., Douguet, D., Feliciangeli, S., Bendahhou, S., Reichold, M., … Lesage, F. (2012). TWIK1, a unique background channel with variable ion selectivity. Proceedings of the National Academy of Sciences of the United States of America, 109(14), 5499–5504. doi:10.1073/pnas.1201132109Find this resource:

Chatelain, F. C., Bichet, D., Feliciangeli, S., Larroque, M. M., Braud, V. M., Douguet, D., & Lesage, F. (2013). Silencing of the tandem pore domain halothane-inhibited K+ channel 2 (THIK2) relies on combined intracellular retention and low intrinsic activity at the plasma membrane. Journal of Biological Chemistry, 288(49), 35081–35092. doi:10.1074/jbc.M113.503318Find this resource:

Chemin, J., Girard, C., Duprat, F., Lesage, F., Romey, G., & Lazdunski, M. (2003). Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO Journal, 22(20), 5403–5411. doi:10.1093/emboj/cdg528Find this resource:

Chemin, J., Patel, A., Duprat, F., Zanzouri, M., Lazdunski, M., & Honore, E. (2005). Lysophosphatidic acid-operated K+ channels. Journal of Biological Chemistry, 280(6), 4415–4421. doi:10.1074/jbc.M408246200Find this resource:

Chemin, J., Patel, A. J., Duprat, F., Lauritzen, I., Lazdunski, M., & Honore, E. (2005). A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO Journal, 24(1), 44–53. doi:10.1038/sj.emboj.7600494Find this resource:

Chemin, J., Patel, A. J., Duprat, F., Sachs, F., Lazdunski, M., & Honore, E. (2007). Up- and down-regulation of the mechano-gated K(2P) channel TREK-1 by PIP (2) and other membrane phospholipids. Pflügers Archiv, 455(1), 97–103. doi:10.1007/s00424-007-0250-2Find this resource:

Chen, H., Chatelain, F. C., & Lesage, F. (2014). Altered and dynamic ion selectivity of K+ channels in cell development and excitability. Trends in Pharmacological Sciences, 35(9), 461–469. doi:10.1016/j.tips.2014.06.002Find this resource:

Chen, X., Talley, E. M., Patel, N., Gomis, A., McIntire, W. E., Dong, B., … Bayliss, D. A. (2006). Inhibition of a background potassium channel by Gq protein alpha-subunits. Proceedings of the National Academy of Sciences of the United States of America, 103(9), 3422–3427. doi:10.1073/pnas.0507710103Find this resource:

Chen, Y., Zeng, X., Huang, X., Serag, S., Woolf, C. J., & Spiegelman, B. M. (2017). Crosstalk between KCNK3-mediated ion current and adrenergic signaling regulates adipose thermogenesis and obesity. Cell, 171(4), 836–848 e813. doi:10.1016/j.cell.2017.09.015Find this resource:

Coburn, C. A., Luo, Y., Cui, M., Wang, J., Soll, R., Dong, J., … Renger, J. J. (2012). Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3). ChemMedChem, 7(1), 123–133. doi:10.1002/cmdc.201100351Find this resource:

Cotten, J. F. (2013). TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore potassium channel antagonists stimulate breathing in isoflurane-anesthetized rats. Anesthesia and Analgesia, 116(4), 810–816. doi:10.1213/ANE.0b013e318284469dFind this resource:

Cotten, J. F., Keshavaprasad, B., Laster, M. J., Eger, E. I., 2nd, & Yost, C. S. (2006). The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration. Anesthesia and Analgesia, 102(3), 779–785. doi:10.1213/01.ane.0000194289.34345.63Find this resource:

Czirjak, G., & Enyedi, P. (2002). TASK-3 dominates the background potassium conductance in rat adrenal glomerulosa cells. Molecular Endocrinology, 16(3), 621–629. doi:10.1210/mend.16.3.0788Find this resource:

Czirjak, G., & Enyedi, P. (2010). TRESK background K(+) channel is inhibited by phosphorylation via two distinct pathways. Journal of Biological Chemistry, 285(19), 14549–14557. doi:10.1074/jbc.M110.102020Find this resource:

Czirjak, G., Fischer, T., Spat, A., Lesage, F., & Enyedi, P. (2000). TASK (TWIK-related acid-sensitive K+ channel) is expressed in glomerulosa cells of rat adrenal cortex and inhibited by angiotensin II. Molecular Endocrinology, 14(6), 863–874. doi:10.1210/mend.14.6.0466Find this resource:

Czirjak, G., Petheo, G. L., Spat, A., & Enyedi, P. (2001). Inhibition of TASK-1 potassium channel by phospholipase C. American Journal of Physiology–Cell Physiology, 281(2), C700–708. doi:10.1152/ajpcell.2001.281.2.C700Find this resource:

Czirjak, G., Toth, Z. E., & Enyedi, P. (2004). The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. Journal of Biological Chemistry, 279(18), 18550–18558. doi:10.1074/jbc.M312229200Find this resource:

Czirjak, G., Vuity, D., & Enyedi, P. (2008). Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. Journal of Biological Chemistry, 283(23), 15672–15680. doi:10.1074/jbc.M800712200Find this resource:

Dadi, P. K., Luo, B., Vierra, N. C., & Jacobson, D. A. (2015). TASK-1 potassium channels limit pancreatic alpha-cell calcium influx and glucagon secretion. Molecular Endocrinology, 29(5), 777–787. doi:10.1210/me.2014-1321Find this resource:

Dadi, P. K., Vierra, N. C., & Jacobson, D. A. (2014). Pancreatic beta-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance. Endocrinology, 155(10), 3757–3768. doi:10.1210/en.2013-2051Find this resource:

Davies, L. A., Hu, C., Guagliardo, N. A., Sen, N., Chen, X., Talley, E. M., … Barrett, P. Q. (2008). TASK channel deletion in mice causes primary hyperaldosteronism. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 2203–2208. doi:10.1073/pnas.0712000105Find this resource:

Decher, N., Kiper, A. K., Rolfes, C., Schulze-Bahr, E., & Rinne, S. (2015). The role of acid-sensitive two-pore domain potassium channels in cardiac electrophysiology: Focus on arrhythmias. Pflügers Archiv, 467(5), 1055–1067. doi:10.1007/s00424-014-1637-5Find this resource:

Dobler, T., Springauf, A., Tovornik, S., Weber, M., Schmitt, A., Sedlmeier, R., … Doring, F. (2007). TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. Journal of Physiology, 585(Pt 3), 867–879. doi:10.1113/jphysiol.2007.145649Find this resource:

Dong, Y. Y., Pike, A. C., Mackenzie, A., McClenaghan, C., Aryal, P., Dong, L., … Carpenter, E. P. (2015). K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science, 347(6227), 1256–1259. doi:10.1126/science.1261512Find this resource:

Du, Y., Kiyoshi, C. M., Wang, Q., Wang, W., Ma, B., Alford, C. C., … Zhou, M. (2016). Genetic deletion of TREK-1 or TWIK-1/TREK-1 potassium channels does not alter the basic electrophysiological properties of mature hippocampal astrocytes in situ. Frontiers in Cellular Neuroscience, 10, 13. doi:10.3389/fncel.2016.00013Find this resource:

Duprat, F., Girard, C., Jarretou, G., & Lazdunski, M. (2005). Pancreatic two P domain K+ channels TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species. Journal of Physiology, 562(Pt 1), 235–244. doi:10.1113/jphysiol.2004.071266Find this resource:

Enyedi, P., & Czirjak, G. (2010). Molecular background of leak K+ currents: Two-pore domain potassium channels. Physiological Reviews, 90(2), 559–605. doi:10.1152/physrev.00029.2009Find this resource:

Fearon, I. M., Campanucci, V. A., Brown, S. T., Hudasek, K., O’Kelly, I. M., & Nurse, C. A. (2006). Acute hypoxic regulation of recombinant THIK-1 stably expressed in HEK293 cells. Advances in Experimental Medicine and Biology, 580, 203–208; discussion 351–209. doi:10.1007/0-387-31311-7_31Find this resource:

Feliciangeli, S., Bendahhou, S., Sandoz, G., Gounon, P., Reichold, M., Warth, R., … Lesage, F. (2007). Does sumoylation control K2P1/TWIK1 background K+ channels? Cell, 130(3), 563–569. doi:10.1016/j.cell.2007.06.012Find this resource:

Feliciangeli, S., Chatelain, F. C., Bichet, D., & Lesage, F. (2015). The family of K2P channels: Salient structural and functional properties. Journal of Physiology, 593(12), 2587–2603. doi:10.1113/jphysiol.2014.287268Find this resource:

Feliciangeli, S., Tardy, M. P., Sandoz, G., Chatelain, F. C., Warth, R., Barhanin, J., … Lesage, F. (2010). Potassium channel silencing by constitutive endocytosis and intracellular sequestration. Journal of Biological Chemistry, 285(7), 4798–4805. doi:10.1074/jbc.M109.078535Find this resource:

Franks, N. P., & Lieb, W. R. (1988). Volatile general anaesthetics activate a novel neuronal K+ current. Nature, 333(6174), 662–664. doi:10.1038/333662a0Find this resource:

Gestreau, C., Heitzmann, D., Thomas, J., Dubreuil, V., Bandulik, S., Reichold, M., … Barhanin, J. (2010). Task2 potassium channels set central respiratory CO2 and O2 sensitivity. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2325–2330. doi:10.1073/pnas.0910059107Find this resource:

Girard, C., Duprat, F., Terrenoire, C., Tinel, N., Fosset, M., Romey, G., … Lesage, F. (2001). Genomic and functional characteristics of novel human pancreatic 2P domain K(+) channels. Biochemical and Biophysical Research Communications, 282(1), 249–256. doi:10.1006/bbrc.2001.4562Find this resource:

Goldstein, M., Rinne, S., Kiper, A. K., Ramirez, D., Netter, M. F., Bustos, D., … Decher, N. (2016). Functional mutagenesis screens reveal the “cap structure” formation in disulfide-bridge free TASK channels. Scientific Reports, 6, 19492. doi:10.1038/srep19492Find this resource:

Goldstein, S. A., Bayliss, D. A., Kim, D., Lesage, F., Plant, L. D., & Rajan, S. (2005). International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacological Reviews, 57(4), 527–540. doi:10.1124/pr.57.4.12Find this resource:

Goldstein, S. A., Bockenhauer, D., O’Kelly, I., & Zilberberg, N. (2001). Potassium leak channels and the KCNK family of two-P-domain subunits. Nature Reviews Neuroscience, 2(3), 175–184. doi:10.1038/35058574Find this resource:

Goldstein, S. A., Price, L. A., Rosenthal, D. N., & Pausch, M. H. (1996). ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America, 93(23), 13256–13261.Find this resource:

Goldstein, S. A., Wang, K. W., Ilan, N., & Pausch, M. H. (1998). Sequence and function of the two P domain potassium channels: Implications of an emerging superfamily. Journal of Molecular Medicine (Berlin), 76(1), 13–20.Find this resource:

Gonzalez, J. A., Jensen, L. T., Doyle, S. E., Miranda-Anaya, M., Menaker, M., Fugger, L., … Burdakov, D. (2009). Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons. European Journal of Neuroscience, 30(1), 57–64. doi:10.1111/j.1460-9568.2009.06789.xFind this resource:

Gu, W., Schlichthorl, G., Hirsch, J. R., Engels, H., Karschin, C., Karschin, A., … Daut, J. (2002). Expression pattern and functional characteristics of two novel splice variants of the two-pore-domain potassium channel TREK-2. Journal of Physiology, 539(Pt 3), 657–668.Find this resource:

Guagliardo, N. A., Yao, J., Hu, C., Schertz, E. M., Tyson, D. A., Carey, R. M., … Barrett, P. Q. (2012). TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension, 59(5), 999–1005. doi:10.1161/HYPERTENSIONAHA.111.189662Find this resource:

Gurney, A. M., Osipenko, O. N., MacMillan, D., McFarlane, K. M., Tate, R. J., & Kempsill, F. E. (2003). Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells. Circulation Research, 93(10), 957–964. doi:10.1161/01.RES.0000099883.68414.61Find this resource:

Guyenet, P. G., & Bayliss, D. A. (2015). Neural control of breathing and CO2 homeostasis. Neuron, 87(5), 946–961. doi:10.1016/j.neuron.2015.08.001Find this resource:

Han, J., Kang, D., & Kim, D. (2003). Functional properties of four splice variants of a human pancreatic tandem-pore K+ channel, TALK-1. American Journal of Physiology–Cell Physiology, 285(3), C529–538. doi:10.1152/ajpcell.00601.2002Find this resource:

Heitzmann, D., Derand, R., Jungbauer, S., Bandulik, S., Sterner, C., Schweda, F., … Barhanin, J. (2008). Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO Journal, 27(1), 179–187. doi:10.1038/sj.emboj.7601934Find this resource:

Heurteaux, C., Guy, N., Laigle, C., Blondeau, N., Duprat, F., Mazzuca, M., … Lazdunski, M. (2004). TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO Journal, 23(13), 2684–2695. doi:10.1038/sj.emboj.7600234Find this resource:

Heurteaux, C., Lucas, G., Guy, N., El Yacoubi, M., Thummler, S., Peng, X. D., … Lazdunski, M. (2006). Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nature Neuroscience, 9(9), 1134–1141. doi:10.1038/nn1749Find this resource:

Honore, E. (2007). The neuronal background K2P channels: Focus on TREK1. Nature Reviews Neuroscience, 8(4), 251–261. doi:10.1038/nrn2117Find this resource:

Honore, E., Maingret, F., Lazdunski, M., & Patel, A. J. (2002). An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK-1. EMBO Journal, 21(12), 2968–2976. doi:10.1093/emboj/cdf288Find this resource:

Hwang, E. M., Kim, E., Yarishkin, O., Woo, D. H., Han, K. S., Park, N., … Park, J. Y. (2014). A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nature Communications, 5, 3227. doi:10.1038/ncomms4227Find this resource:

Ishii, H., Nakajo, K., Yanagawa, Y., & Kubo, Y. (2010). Identification and characterization of Cs(+)—permeable K(+) channel current in mouse cerebellar Purkinje cells in lobules 9 and 10 evoked by molecular layer stimulation. European Journal of Neuroscience, 32(5), 736–748. doi:10.1111/j.1460-9568.2010.07336.xFind this resource:

Jiang, Y., Lee, A., Chen, J., Ruta, V., Cadene, M., Chait, B. T., & MacKinnon, R. (2003). X-ray structure of a voltage-dependent K+ channel. Nature, 423(6935), 33–41. doi:10.1038/nature01580Find this resource:

Kang, D., Choe, C., Cavanaugh, E., & Kim, D. (2007). Properties of single two-pore domain TREK-2 channels expressed in mammalian cells. Journal of Physiology, 583(Pt 1), 57–69. doi:10.1113/jphysiol.2007.136150Find this resource:

Kang, D., Choe, C., & Kim, D. (2005). Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. Journal of Physiology, 564(Pt 1), 103–116. doi:10.1113/jphysiol.2004.081059Find this resource:

Kang, D., Han, J., & Kim, D. (2006). Mechanism of inhibition of TREK-2 (K2P10.1) by the Gq-coupled M3 muscarinic receptor. American Journal of Physiology–Cell Physiology, 291(4), C649–656. doi:10.1152/ajpcell.00047.2006Find this resource:

Kang, D., Han, J., Talley, E. M., Bayliss, D. A., & Kim, D. (2004). Functional expression of TASK-1/TASK-3 heteromers in cerebellar granule cells. Journal of Physiology, 554(Pt 1), 64–77. doi:10.1113/jphysiol.2003.054387Find this resource:

Kang, D., Hogan, J. O., & Kim, D. (2014). THIK-1 (K2P13.1) is a small-conductance background K(+) channel in rat trigeminal ganglion neurons. Pflügers Archiv, 466(7), 1289–1300. doi:10.1007/s00424-013-1358-1Find this resource:

Kang, D., & Kim, D. (2004). Single-channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochemical and Biophysical Research Communications, 315(4), 836–844. doi:10.1016/j.bbrc.2004.01.137Find this resource:

Kang, D., & Kim, D. (2006). TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. American Journal of Physiology–Cell Physiology, 291(1), C138–146. doi:10.1152/ajpcell.00629.2005Find this resource:

Kang, D., Mariash, E., & Kim, D. (2004). Functional expression of TRESK-2, a new member of the tandem-pore K+ channel family. Journal of Biological Chemistry, 279(27), 28063–28070. doi:10.1074/jbc.M402940200Find this resource:

Karschin, C., Wischmeyer, E., Preisig-Muller, R., Rajan, S., Derst, C., Grzeschik, K. H., … Karschin, A. (2001). Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K(+) channel subunit, TASK-5, associated with the central auditory nervous system. Molecular and Cellular Neuroscience, 18(6), 632–648. doi:10.1006/mcne.2001.1045Find this resource:

Kennard, L. E., Chumbley, J. R., Ranatunga, K. M., Armstrong, S. J., Veale, E. L., & Mathie, A. (2005). Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. British Journal of Pharmacology, 144(6), 821–829. doi:10.1038/sj.bjp.0706068Find this resource:

Keshavaprasad, B., Liu, C., Au, J. D., Kindler, C. H., Cotten, J. F., & Yost, C. S. (2005). Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK. Anesthesia and Analgesia, 101(4), 1042–1049, Table of Contents. doi:10.1213/01.ane.0000168447.87557.5aFind this resource:

Kilisch, M., Lytovchenko, O., Schwappach, B., Renigunta, V., & Daut, J. (2015). The role of protein–protein interactions in the intracellular traffic of the potassium channels TASK-1 and TASK-3. Pflügers Archiv, 467(5), 1105–1120. doi:10.1007/s00424-014-1672-2Find this resource:

Kim, D. (2005). Physiology and pharmacology of two-pore domain potassium channels. Current Pharmaceutical Design, 11(21), 2717–2736.Find this resource:

Kim, D. (2013). K(+) channels in O(2) sensing and postnatal development of carotid body glomus cell response to hypoxia. Respiration Physiology and Neurobiology, 185(1), 44–56. doi:10.1016/j.resp.2012.07.005Find this resource:

Kim, D., Cavanaugh, E. J., Kim, I., & Carroll, J. L. (2009). Heteromeric TASK-1/TASK-3 is the major oxygen-sensitive background K+ channel in rat carotid body glomus cells. Journal of Physiology, 587(Pt 12), 2963–2975. doi:10.1113/jphysiol.2009.171181Find this resource:

Kim, D., & Gnatenco, C. (2001). TASK-5, a new member of the tandem-pore K(+) channel family. Biochemical and Biophysical Research Communications, 284(4), 923–930. doi:10.1006/bbrc.2001.5064Find this resource:

Kim, Y., Bang, H., & Kim, D. (1999). TBAK-1 and TASK-1, two-pore K(+) channel subunits: Kinetic properties and expression in rat heart. American Journal of Physiology, 277(5 Pt 2), H1669–1678.Find this resource:

Kim, Y., Bang, H., & Kim, D. (2000). TASK-3, a new member of the tandem pore K(+) channel family. Journal of Biological Chemistry, 275(13), 9340–9347.Find this resource:

Koo, J. Y., Jang, Y., Cho, H., Lee, C. H., Jang, K. H., Chang, Y. H., … Oh, U. (2007). Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. European Journal of Neuroscience, 26(5), 1139–1147. doi:10.1111/j.1460-9568.2007.05743.xFind this resource:

Kreneisz, O., Benoit, J. P., Bayliss, D. A., & Mulkey, D. K. (2009). AMP-activated protein kinase inhibits TREK channels. Journal of Physiology, 587(Pt 24), 5819–5830. doi:10.1113/jphysiol.2009.180372Find this resource:

Kumar, N. N., Velic, A., Soliz, J., Shi, Y., Li, K., Wang, S., … Bayliss, D. A. (2015). PHYSIOLOGY. Regulation of breathing by CO(2) requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science, 348(6240), 1255–1260. doi:10.1126/science.aaa0922Find this resource:

Lafreniere, R. G., Cader, M. Z., Poulin, J. F., Andres-Enguix, I., Simoneau, M., Gupta, N., … Rouleau, G. A. (2010). A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine, 16(10), 1157–1160. doi:10.1038/nm.2216Find this resource:

Lambert, M., Boet, A., Rucker-Martin, C., Mendes-Ferreira, P., Capuano, V., Hatem, S., … Antigny, F. (2018). Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension. Cardiovascular Research 114(6): 880–893. doi:10.1093/cvr/cvy016Find this resource:

Lazarenko, R. M., Fortuna, M. G., Shi, Y., Mulkey, D. K., Takakura, A. C., Moreira, T. S., … Bayliss, D. A. (2010). Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current. Journal of Neuroscience, 30(27), 9324–9334. doi:10.1523/JNEUROSCI.1956-10.2010Find this resource:

Lazarenko, R. M., Willcox, S. C., Shu, S., Berg, A. P., Jevtovic-Todorovic, V., Talley, E. M., … Bayliss, D. A. (2010). Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics. Journal of Neuroscience, 30(22), 7691–7704. doi:10.1523/JNEUROSCI.1655-10.2010Find this resource:

Lengyel, M., Czirjak, G., & Enyedi, P. (2016). Formation of functional heterodimers by TREK-1 and TREK-2 two-pore domain potassium channel subunits. Journal of Biological Chemistry, 291(26), 13649–13661. doi:10.1074/jbc.M116.719039Find this resource:

Lesage, F., & Barhanin, J. (2011). Molecular physiology of pH-sensitive background K(2P) channels. Physiology (Bethesda), 26(6), 424–437. doi:10.1152/physiol.00029.2011Find this resource:

Lesage, F., Guillemare, E., Fink, M., Duprat, F., Lazdunski, M., Romey, G., & Barhanin, J. (1996). TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO Journal, 15(5), 1004–1011.Find this resource:

Lesage, F., Lauritzen, I., Duprat, F., Reyes, R., Fink, M., Heurteaux, C., & Lazdunski, M. (1997). The structure, function and distribution of the mouse TWIK-1 K+ channel. FEBS Letters, 402(1), 28–32.Find this resource:

Lesage, F., & Lazdunski, M. (2000). Molecular and functional properties of two-pore-domain potassium channels. American Journal of Physiology–Renal Physiology, 279(5), F793–801. doi:10.1152/ajprenal.2000.279.5.F793Find this resource:

Lesage, F., Reyes, R., Fink, M., Duprat, F., Guillemare, E., & Lazdunski, M. (1996). Dimerization of TWIK-1 K+ channel subunits via a disulfide bridge. EMBO Journal, 15(23), 6400–6407.Find this resource:

Lesage, F., Terrenoire, C., Romey, G., & Lazdunski, M. (2000). Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. Journal of Biological Chemistry, 275(37), 28398–28405. doi:10.1074/jbc.M002822200Find this resource:

Levitz, J., Royal, P., Comoglio, Y., Wdziekonski, B., Schaub, S., Clemens, D. M., … Sandoz, G. (2016). Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proceedings of the National Academy of Sciences of the United States of America, 113(15), 4194–4199. doi:10.1073/pnas.1522459113Find this resource:

Linden, A. M., Aller, M. I., Leppa, E., Vekovischeva, O., Aitta-Aho, T., Veale, E. L., … Korpi, E. R. (2006). The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists. Journal of Pharmacology and Experimental Therapeutics, 317(2), 615–626. doi:10.1124/jpet.105.098525Find this resource:

Linden, A. M., Sandu, C., Aller, M. I., Vekovischeva, O. Y., Rosenberg, P. H., Wisden, W., & Korpi, E. R. (2007). TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. Journal of Pharmacology and Experimental Therapeutics, 323(3), 924–934. doi:10.1124/jpet.107.129544Find this resource:

Lindner, M., Leitner, M. G., Halaszovich, C. R., Hammond, G. R., & Oliver, D. (2011). Probing the regulation of TASK potassium channels by PI4,5P(2) with switchable phosphoinositide phosphatases. Journal of Physiology, 589(Pt 13), 3149–3162. doi:10.1113/jphysiol.2011.208983Find this resource:

Liu, C., Au, J. D., Zou, H. L., Cotten, J. F., & Yost, C. S. (2004). Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesthesia and Analgesia, 99(6), 1715–1722, Table of Contents. doi:10.1213/01.ANE.0000136849.07384.44Find this resource:

Lolicato, M., Arrigoni, C., Mori, T., Sekioka, Y., Bryant, C., Clark, K. A., & Minor, D. L., Jr. (2017). K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Nature, 547(7663), 364–368. doi:10.1038/nature22988Find this resource:

Lopes, C. M., Rohacs, T., Czirjak, G., Balla, T., Enyedi, P., & Logothetis, D. E. (2005). PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. Journal of Physiology, 564(Pt 1), 117–129. doi:10.1113/jphysiol.2004.081935Find this resource:

Lopes, C. M., Zilberberg, N., & Goldstein, S. A. (2001). Block of Kcnk3 by protons. Evidence that 2-P-domain potassium channel subunits function as homodimers. Journal of Biological Chemistry, 276(27), 24449–24452. doi:10.1074/jbc.C100184200Find this resource:

Ma, L., Zhang, X., & Chen, H. (2011). TWIK-1 two-pore domain potassium channels change ion selectivity and conduct inward leak sodium currents in hypokalemia. Science Signaling, 4(176), ra37. doi:10.1126/scisignal.2001726Find this resource:

Madrid, R., de la Pena, E., Donovan-Rodriguez, T., Belmonte, C., & Viana, F. (2009). Variable threshold of trigeminal cold-thermosensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels. Journal of Neuroscience, 29(10), 3120–3131. doi:10.1523/JNEUROSCI.4778-08.2009Find this resource:

Madry, C., Kyrargyri, V., Arancibia-Cárcamo, I.L., Jolivet, R., Kohsaka, S., Bryan, R.M., Attwell, D. (2018). Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K+ channel THIK-1. Neuron. 97(2), 299–312. doi: 10.1016/j.neuron.2017.12.002.Find this resource:

Maingret, F., Fosset, M., Lesage, F., Lazdunski, M., & Honore, E. (1999). TRAAK is a mammalian neuronal mechano-gated K+ channel. Journal of Biological Chemistry, 274(3), 1381–1387.Find this resource:

Maingret, F., Lauritzen, I., Patel, A. J., Heurteaux, C., Reyes, R., Lesage, F., … Honore, E. (2000). TREK-1 is a heat-activated background K(+) channel. EMBO Journal, 19(11), 2483–2491. doi:10.1093/emboj/19.11.2483Find this resource:

Maingret, F., Patel, A. J., Lesage, F., Lazdunski, M., & Honore, E. (1999). Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. Journal of Biological Chemistry, 274(38), 26691–26696.Find this resource:

Maingret, F., Patel, A. J., Lesage, F., Lazdunski, M., & Honore, E. (2000). Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. Journal of Biological Chemistry, 275(14), 10128–10133.Find this resource:

Manoury, B., Lamalle, C., Oliveira, R., Reid, J., & Gurney, A. M. (2011). Contractile and electrophysiological properties of pulmonary artery smooth muscle are not altered in TASK-1 knockout mice. Journal of Physiology, 589(Pt 13), 3231–3246. doi:10.1113/jphysiol.2011.206748Find this resource:

Marinc, C., Preisig-Muller, R., Pruss, H., Derst, C., & Veh, R. W. (2011). Immunocytochemical localization of TASK-3 (K(2P)9.1) channels in monoaminergic and cholinergic neurons. Cellular and Molecular Neurobiology, 31(2), 323–335. doi:10.1007/s10571-010-9625-6Find this resource:

Mathie, A. (2007). Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. Journal of Physiology, 578(Pt 2), 377–385. doi:10.1113/jphysiol.2006.121582Find this resource:

Mazella, J., Petrault, O., Lucas, G., Deval, E., Beraud-Dufour, S., Gandin, C., … Borsotto, M. (2010). Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: A new concept in the antidepressant drug design. PLoS Biology, 8(4), e1000355. doi:10.1371/journal.pbio.1000355Find this resource:

McClenaghan, C., Schewe, M., Aryal, P., Carpenter, E. P., Baukrowitz, T., & Tucker, S. J. (2016). Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states. Journal of General Physiology, 147(6), 497–505. doi:10.1085/jgp.201611601Find this resource:

Medhurst, A. D., Rennie, G., Chapman, C. G., Meadows, H., Duckworth, M. D., Kelsell, R. E., … Pangalos, M. N. (2001). Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Brain Research, Molecular Brain Research, 86(1–2), 101–114.Find this resource:

Meuth, S. G., Budde, T., Kanyshkova, T., Broicher, T., Munsch, T., & Pape, H. C. (2003). Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons. Journal of Neuroscience, 23(16), 6460–6469.Find this resource:

Meuth, S. G., Kleinschnitz, C., Broicher, T., Austinat, M., Braeuninger, S., Bittner, S., … Wiendl, H. (2009). The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice. Neurobiology of Disease, 33(1), 1–11. doi:10.1016/j.nbd.2008.09.006Find this resource:

Millar, J. A., Barratt, L., Southan, A. P., Page, K. M., Fyffe, R. E., Robertson, B., & Mathie, A. (2000). A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proceedings of the National Academy of Sciences of the United States of America, 97(7), 3614–3618. doi:10.1073/pnas.050012597Find this resource:

Miller, A. N., & Long, S. B. (2012). Crystal structure of the human two-pore domain potassium channel K2P1. Science, 335(6067), 432–436. doi:10.1126/science.1213274Find this resource:

Mirkovic, K., & Wickman, K. (2011). Identification and characterization of alternative splice variants of the mouse Trek2/Kcnk10 gene. Neuroscience, 194, 11–18. doi:10.1016/j.neuroscience.2011.07.064Find this resource:

Moore, J. T., Chen, J., Han, B., Meng, Q. C., Veasey, S. C., Beck, S. G., & Kelz, M. B. (2012). Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. Current Biology, 22(21), 2008–2016. doi:10.1016/j.cub.2012.08.042Find this resource:

Morenilla-Palao, C., Luis, E., Fernandez-Pena, C., Quintero, E., Weaver, J. L., Bayliss, D. A., & Viana, F. (2014). Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Reports, 8(5), 1571–1582. doi:10.1016/j.celrep.2014.08.003Find this resource:

Mulkey, D. K., Talley, E. M., Stornetta, R. L., Siegel, A. R., West, G. H., Chen, X., … Bayliss, D. A. (2007). TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. Journal of Neuroscience, 27(51), 14049–14058. doi:10.1523/JNEUROSCI.4254-07.2007Find this resource:

Murbartian, J., Lei, Q., Sando, J. J., & Bayliss, D. A. (2005). Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. Journal of Biological Chemistry, 280(34), 30175–30184. doi:10.1074/jbc.M503862200Find this resource:

Murtaza, G., Mermer, P., Goldenberg, A., Pfeil, U., Paddenberg, R., Weissmann, N., … Kummer, W. (2017). TASK-1 potassium channel is not critically involved in mediating hypoxic pulmonary vasoconstriction of murine intra-pulmonary arteries. PLoS One, 12(3), e0174071. doi:10.1371/journal.pone.0174071Find this resource:

Nicoll, R. A. (1988). The coupling of neurotransmitter receptors to ion channels in the brain. Science, 241(4865), 545–551.Find this resource:

Nicoll, R. A., & Madison, D. V. (1982). General anesthetics hyperpolarize neurons in the vertebrate central nervous system. Science, 217(4564), 1055–1057.Find this resource:

Nicoll, R. A., Malenka, R. C., & Kauer, J. A. (1990). Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiological Reviews, 70(2), 513–565. doi:10.1152/physrev.1990.70.2.513Find this resource:

Niemeyer, M. I., Gonzalez-Nilo, F. D., Zuniga, L., Gonzalez, W., Cid, L. P., & Sepulveda, F. V. (2007). Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel. Proceedings of the National Academy of Sciences of the United States of America, 104(2), 666–671. doi:10.1073/pnas.0606173104Find this resource:

Noel, J., Zimmermann, K., Busserolles, J., Deval, E., Alloui, A., Diochot, S., … Lazdunski, M. (2009). The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. EMBO Journal, 28(9), 1308–1318. doi:10.1038/emboj.2009.57Find this resource:

O’Kelly, I., Butler, M. H., Zilberberg, N., & Goldstein, S. A. (2002). Forward transport. 14-3-3 binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell, 111(4), 577–588.Find this resource:

Olschewski, A., Li, Y., Tang, B., Hanze, J., Eul, B., Bohle, R. M., … Olschewski, H. (2006). Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circulation Research, 98(8), 1072–1080. doi:10.1161/01.RES.0000219677.12988.e9Find this resource:

Ortega-Saenz, P., Levitsky, K. L., Marcos-Almaraz, M. T., Bonilla-Henao, V., Pascual, A., & Lopez-Barneo, J. (2010). Carotid body chemosensory responses in mice deficient of TASK channels. Journal of General Physiology, 135(4), 379–392. doi:10.1085/jgp.200910302Find this resource:

Pang, D. S., Robledo, C. J., Carr, D. R., Gent, T. C., Vyssotski, A. L., Caley, A., … Franks, N. P. (2009). An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17546–17551. doi:10.1073/pnas.0907228106Find this resource:

Patel, A., & Honore, E. (2002). The TREK two P domain K+ channels. Journal of Physiology, 539(Pt 3), 647.Find this resource:

Patel, A. J., Honore, E., Lesage, F., Fink, M., Romey, G., & Lazdunski, M. (1999). Inhalational anesthetics activate two-pore-domain background K+ channels. Nature Neuroscience, 2(5), 422–426. doi:10.1038/8084Find this resource:

Patel, A. J., Honore, E., Maingret, F., Lesage, F., Fink, M., Duprat, F., & Lazdunski, M. (1998). A mammalian two pore domain mechano-gated S-like K+ channel. EMBO Journal, 17(15), 4283–4290. doi:10.1093/emboj/17.15.4283Find this resource:

Patel, A. J., Lazdunski, M., & Honore, E. (2001). Lipid and mechano-gated 2P domain K(+) channels. Current Opinion in Cell Biology, 13(4), 422–428.Find this resource:

Patel, A. J., Maingret, F., Magnone, V., Fosset, M., Lazdunski, M., & Honore, E. (2000). TWIK-2, an inactivating 2P domain K+ channel. Journal of Biological Chemistry, 275(37), 28722–28730. doi:10.1074/jbc.M003755200Find this resource:

Penton, D., Bandulik, S., Schweda, F., Haubs, S., Tauber, P., Reichold, M., … Barhanin, J. (2012). Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology, 153(10), 4740–4748. doi:10.1210/en.2012-1527Find this resource:

Pereira, V., Busserolles, J., Christin, M., Devilliers, M., Poupon, L., Legha, W., … Noel, J. (2014). Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception. Pain, 155(12), 2534–2544. doi:10.1016/j.pain.2014.09.013Find this resource:

Piechotta, P. L., Rapedius, M., Stansfeld, P. J., Bollepalli, M. K., Ehrlich, G., Andres-Enguix, I., … Baukrowitz, T. (2011). The pore structure and gating mechanism of K2P channels. EMBO Journal, 30(17), 3607–3619. doi:10.1038/emboj.2011.268Find this resource:

Pisani, D. F., Beranger, G. E., Corinus, A., Giroud, M., Ghandour, R. A., Altirriba, J., … Amri, E. Z. (2016). The K+ channel TASK1 modulates beta-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway. FASEB Journal, 30(2), 909–922. doi:10.1096/fj.15-277475Find this resource:

Plant, L. D., Dementieva, I. S., Kollewe, A., Olikara, S., Marks, J. D., & Goldstein, S. A. (2010). One SUMO is sufficient to silence the dimeric potassium channel K2P1. Proceedings of the National Academy of Sciences of the United States of America, 107(23), 10743–10748. doi:10.1073/pnas.1004712107Find this resource:

Plant, L. D., Zuniga, L., Araki, D., Marks, J. D., & Goldstein, S. A. (2012). SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Science Signaling, 5(251), ra84. doi:10.1126/scisignal.2003431Find this resource:

Rajan, S., Plant, L. D., Rabin, M. L., Butler, M. H., & Goldstein, S. A. (2005). Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell, 121(1), 37–47. doi:10.1016/j.cell.2005.01.019Find this resource:

Rajan, S., Preisig-Muller, R., Wischmeyer, E., Nehring, R., Hanley, P. J., Renigunta, V., … Daut, J. (2002). Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. Journal of Physiology, 545(Pt 1), 13–26.Find this resource:

Rajan, S., Wischmeyer, E., Karschin, C., Preisig-Muller, R., Grzeschik, K. H., Daut, J., … Derst, C. (2001). THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. Journal of Biological Chemistry, 276(10), 7302–7311. doi:10.1074/jbc.M008985200Find this resource:

Rajan, S., Wischmeyer, E., Xin Liu, G., Preisig-Muller, R., Daut, J., Karschin, A., & Derst, C. (2000). TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histidine as pH sensor. Journal of Biological Chemistry, 275(22), 16650–16657. doi:10.1074/jbc.M000030200Find this resource:

Renigunta, V., Schlichthorl, G., & Daut, J. (2015). Much more than a leak: Structure and function of K(2)p-channels. Pflügers Archiv, 467(5), 867–894. doi:10.1007/s00424-015-1703-7Find this resource:

Renigunta, V., Yuan, H., Zuzarte, M., Rinne, S., Koch, A., Wischmeyer, E., … Preisig-Muller, R. (2006). The retention factor p11 confers an endoplasmic reticulum-localization signal to the potassium channel TASK-1. Traffic, 7(2), 168–181. doi:10.1111/j.1600-0854.2005.00375.xFind this resource:

Renigunta, V., Zou, X., Kling, S., Schlichthorl, G., & Daut, J. (2014). Breaking the silence: Functional expression of the two-pore-domain potassium channel THIK-2. Pflügers Archiv, 466(9), 1735–1745. doi:10.1007/s00424-013-1404-zFind this resource:

Reyes, R., Duprat, F., Lesage, F., Fink, M., Salinas, M., Farman, N., & Lazdunski, M. (1998). Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. Journal of Biological Chemistry, 273(47), 30863–30869.Find this resource:

Riera, C. E., Menozzi-Smarrito, C., Affolter, M., Michlig, S., Munari, C., Robert, F., … le Coutre, J. (2009). Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. British Journal of Pharmacology, 157(8), 1398–1409. doi:10.1111/j.1476-5381.2009.00307.xFind this resource:

Rinne, S., Kiper, A. K., Schlichthorl, G., Dittmann, S., Netter, M. F., Limberg, S. H., … Decher, N. (2015). TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. Journal of Molecular and Cellular Cardiology, 81, 71–80. doi:10.1016/j.yjmcc.2015.01.017Find this resource:

Rinne, S., Renigunta, V., Schlichthorl, G., Zuzarte, M., Bittner, S., Meuth, S. G., … Preisig-Muller, R. (2014). A splice variant of the two-pore domain potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels. Pflügers Archiv, 466(8), 1559–1570. doi:10.1007/s00424-013-1384-zFind this resource:

Salinas, M., Reyes, R., Lesage, F., Fosset, M., Heurteaux, C., Romey, G., & Lazdunski, M. (1999). Cloning of a new mouse two-P domain channel subunit and a human homologue with a unique pore structure. Journal of Biological Chemistry, 274(17), 11751–11760.Find this resource:

Sandoz, G., Douguet, D., Chatelain, F., Lazdunski, M., & Lesage, F. (2009). Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14628–14633. doi:10.1073/pnas.0906267106Find this resource:

Sandoz, G., Tardy, M. P., Thummler, S., Feliciangeli, S., Lazdunski, M., & Lesage, F. (2008). Mtap2 is a constituent of the protein network that regulates TWIK-related K+ channel expression and trafficking. Journal of Neuroscience, 28(34), 8545–8552. doi:10.1523/JNEUROSCI.1962-08.2008Find this resource:

Sandoz, G., Thummler, S., Duprat, F., Feliciangeli, S., Vinh, J., Escoubas, P., … Lesage, F. (2006). AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels. EMBO Journal, 25(24), 5864–5872. doi:10.1038/sj.emboj.7601437Find this resource:

Sano, Y., Inamura, K., Miyake, A., Mochizuki, S., Kitada, C., Yokoi, H., … Furuichi, K. (2003). A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. Journal of Biological Chemistry, 278(30), 27406–27412. doi:10.1074/jbc.M206810200Find this resource:

Schewe, M., Nematian-Ardestani, E., Sun, H., Musinszki, M., Cordeiro, S., Bucci, G., … Baukrowitz, T. (2016). A non-canonical voltage-sensing mechanism controls gating in K2P K(+) channels. Cell, 164(5), 937–949. doi:10.1016/j.cell.2016.02.002Find this resource:

Sepulveda, F. V., Pablo Cid, L., Teulon, J., & Niemeyer, M. I. (2015). Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels. Physiological Reviews, 95(1), 179–217. doi:10.1152/physrev.00016.2014Find this resource:

Simkin, D., Cavanaugh, E. J., & Kim, D. (2008). Control of the single channel conductance of K2P10.1 (TREK-2) by the amino-terminus: Role of alternative translation initiation. Journal of Physiology, 586(23), 5651–5663. doi:10.1113/jphysiol.2008.161927Find this resource:

Sirois, J. E., Lei, Q., Talley, E. M., Lynch, C., 3rd, & Bayliss, D. A. (2000). The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. Journal of Neuroscience, 20(17), 6347–6354.Find this resource:

Sirois, J. E., Lynch, C., 3rd, & Bayliss, D. A. (2002). Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones. Journal of Physiology, 541(Pt 3), 717–729.Find this resource:

Staudacher, K., Baldea, I., Kisselbach, J., Staudacher, I., Rahm, A. K., Schweizer, P. A., … Thomas, D. (2011). Alternative splicing determines mRNA translation initiation and function of human K(2P)10.1 K+ channels. Journal of Physiology, 589(Pt 15), 3709–3720. doi:10.1113/jphysiol.2011.210666Find this resource:

Steinberg, E. A., Wafford, K. A., Brickley, S. G., Franks, N. P., & Wisden, W. (2015). The role of K(2)p channels in anaesthesia and sleep. Pflügers Archiv, 467(5), 907–916. doi:10.1007/s00424-014-1654-4Find this resource:

Talley, E. M., & Bayliss, D. A. (2002). Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: Volatile anesthetics and neurotransmitters share a molecular site of action. Journal of Biological Chemistry, 277(20), 17733–17742. doi:10.1074/jbc.M200502200Find this resource:

Talley, E. M., Lei, Q., Sirois, J. E., & Bayliss, D. A. (2000). TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron, 25(2), 399–410.Find this resource:

Talley, E. M., Sirois, J. E., Lei, Q., & Bayliss, D. A. (2003). Two-pore-domain (KCNK) potassium channels: Dynamic roles in neuronal function. Neuroscientist, 9(1), 46–56. doi:10.1177/1073858402239590Find this resource:

Talley, E. M., Solorzano, G., Lei, Q., Kim, D., & Bayliss, D. A. (2001). CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. Journal of Neuroscience, 21(19), 7491–7505.Find this resource:

Thomas, D., Plant, L. D., Wilkens, C. M., McCrossan, Z. A., & Goldstein, S. A. (2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron, 58(6), 859–870. doi:10.1016/j.neuron.2008.04.016Find this resource:

Trapp, S., Aller, M. I., Wisden, W., & Gourine, A. V. (2008). A role for TASK-1 (KCNK3) channels in the chemosensory control of breathing. Journal of Neuroscience, 28(35), 8844–8850. doi:10.1523/JNEUROSCI.1810-08.2008Find this resource:

Tsunozaki, M., Lennertz, R. C., Vilceanu, D., Katta, S., Stucky, C. L., & Bautista, D. M. (2013). A “toothache tree” alkylamide inhibits Adelta mechanonociceptors to alleviate mechanical pain. Journal of Physiology, 591(13), 3325–3340. doi:10.1113/jphysiol.2013.252106Find this resource:

Tulleuda, A., Cokic, B., Callejo, G., Saiani, B., Serra, J., & Gasull, X. (2011). TRESK channel contribution to nociceptive sensory neurons excitability: Modulation by nerve injury. Molecular Pain, 7, 30. doi:10.1186/1744-8069-7-30Find this resource:

Turner, P. J., & Buckler, K. J. (2013). Oxygen and mitochondrial inhibitors modulate both monomeric and heteromeric TASK-1 and TASK-3 channels in mouse carotid body type-1 cells. Journal of Physiology, 591(23), 5977–5998. doi:10.1113/jphysiol.2013.262022Find this resource:

Veale, E. L., Hassan, M., Walsh, Y., Al-Moubarak, E., & Mathie, A. (2014). Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Molecular Pharmacology, 85(3), 397–407. doi:10.1124/mol.113.090530Find this resource:

Veale, E. L., Kennard, L. E., Sutton, G. L., MacKenzie, G., Sandu, C., & Mathie, A. (2007). G(alpha)q-mediated regulation of TASK3 two-pore domain potassium channels: The role of protein kinase C. Molecular Pharmacology, 71(6), 1666–1675. doi:10.1124/mol.106.033241Find this resource:

Veale, E. L., Rees, K. A., Mathie, A., & Trapp, S. (2010). Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain. Journal of Biological Chemistry, 285(38), 29295–29304. doi:10.1074/jbc.M110.108423Find this resource:

Viana, F., de la Pena, E., & Belmonte, C. (2002). Specificity of cold thermotransduction is determined by differential ionic channel expression. Nature Neuroscience, 5(3), 254–260. doi:10.1038/nn809Find this resource:

Vierra, N. C., Dadi, P. K., Jeong, I., Dickerson, M., Powell, D. R., & Jacobson, D. A. (2015). Type 2 diabetes-associated K+ channel TALK-1 modulates beta-cell electrical excitability, second-phase insulin secretion, and glucose homeostasis. Diabetes, 64(11), 3818–3828. doi:10.2337/db15-0280Find this resource:

Vivier, D., Soussia, I. B., Rodrigues, N., Lolignier, S., Devilliers, M., Chatelain, F. C., … Ducki, S. (2017). Development of the first two-pore domain potassium channel TWIK-Related K(+) channel 1-selective agonist possessing in vivo antinociceptive activity. Journal of Medicinal Chemistry, 60(3), 1076–1088. doi:10.1021/acs.jmedchem.6b01285Find this resource:

Vu, M. T., Du, G., Bayliss, D. A., & Horner, R. L. (2015). TASK channels on basal forebrain cholinergic neurons modulate electrocortical signatures of arousal by histamine. Journal of Neuroscience, 35(40), 13555–13567. doi:10.1523/JNEUROSCI.1445-15.2015Find this resource:

Wang, S., Benamer, N., Zanella, S., Kumar, N. N., Shi, Y., Bevengut, M., … Bayliss, D. A. (2013). TASK-2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons. Journal of Neuroscience, 33(41), 16033–16044. doi:10.1523/JNEUROSCI.2451-13.2013Find this resource:

Wang, W., Kiyoshi, C. M., Du, Y., Ma, B., Alford, C. C., Chen, H., & Zhou, M. (2016). mGluR3 activation recruits cytoplasmic TWIK-1 channels to membrane that enhances ammonium uptake in hippocampal astrocytes. Molecular Neurobiology, 53(9), 6169–6182. doi:10.1007/s12035-015-9496-4Find this resource:

Warth, R., Barriere, H., Meneton, P., Bloch, M., Thomas, J., Tauc, M., … Barhanin, J. (2004). Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8215–8220. doi:10.1073/pnas.0400081101Find this resource:

Washburn, C. P., Sirois, J. E., Talley, E. M., Guyenet, P. G., & Bayliss, D. A. (2002). Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. Journal of Neuroscience, 22(4), 1256–1265.Find this resource:

Wilke, B. U., Lindner, M., Greifenberg, L., Albus, A., Kronimus, Y., Bunemann, M., … Oliver, D. (2014). Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors. Nature Communications, 5, 5540. doi:10.1038/ncomms6540Find this resource:

Woo, D. H., Han, K. S., Shim, J. W., Yoon, B. E., Kim, E., Bae, J. Y., … Lee, C. J. (2012). TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell, 151(1), 25–40. doi:10.1016/j.cell.2012.09.005Find this resource:

Yao, C., Li, Y., Shu, S., Yao, S., Lynch, C., Bayliss, D. A., & Chen, X. (2017). TASK channels contribute to neuroprotective action of inhalational anesthetics. Scientific Reports, 7, 44203. doi:10.1038/srep44203Find this resource:

Yao, J., McHedlishvili, D., McIntire, W. E., Guagliardo, N. A., Erisir, A., Coburn, C. A., … Barrett, P. Q. (2017). Functional TASK-3-like channels in mitochondria of aldosterone-producing zona glomerulosa cells. Hypertension, 70(2), 347–356. doi:10.1161/HYPERTENSIONAHA.116.08871Find this resource:

Zhou, J., Yang, C. X., Zhong, J. Y., & Wang, H. B. (2013). Intrathecal TRESK gene recombinant adenovirus attenuates spared nerve injury-induced neuropathic pain in rats. Neuroreport, 24(3), 131–136. doi:10.1097/WNR.0b013e32835d8431Find this resource:

Zhou, M., Xu, G., Xie, M., Zhang, X., Schools, G. P., Ma, L., … Chen, H. (2009). TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. Journal of Neuroscience, 29(26), 8551–8564. doi:10.1523/JNEUROSCI.5784-08.2009Find this resource:

Zuzarte, M., Heusser, K., Renigunta, V., Schlichthorl, G., Rinne, S., Wischmeyer, E., … Preisig-Muller, R. (2009). Intracellular traffic of the K+ channels TASK-1 and TASK-3: Role of N- and C-terminal sorting signals and interaction with 14-3-3 proteins. Journal of Physiology, 587(Pt 5), 929–952. doi:10.1113/jphysiol.2008.164756Find this resource: