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.
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).
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
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.
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).
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.
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.
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.
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.
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.
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.
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