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date: 26 May 2019

The Voltage-Dependent K+ Channel Family

Abstract and Keywords

Voltage-dependent K+ (potassium; Kv) channels are ion channels that critically impact neuronal excitability and function. Four principal α subunits assemble to create a membrane-spanning pore that opens in a voltage-dependent manner to allow the selective passage of K+ ions across the cell membrane. Forty human genes encoding Kv channel α subunits have been identified, and most of them are expressed in the nervous system. The individual Kv subunits display unique cellular and subcellular expression patterns and co-assemble into distinct homo- and hetero-tetrameric channels that differ in their electrophysiological and pharmacological properties, and their sensitivity to dynamic modulation, by cellular signaling pathways. The resulting diversity allows Kv channels to impact all steps in electrical information processing, as well as numerous other aspects of neuronal functions, including those in which they appear to play a non-conducting role. This chapter reviews the current basic knowledge about this large and important family of ion channels.

Keywords: Kv channels, Kvbeta, KChIP, DPPL, AMIGO-1, calmodulin, structure, subcellular localization, neurons

Introduction

Ionic currents originating from voltage-dependent K+ (Kv) channels were first described by Hodgkin and Huxley in 1952 (Hodgkin & Huxley, 1952). In these classical experiments, they deduced the ionic currents underlying the neuronal action potential by performing voltage-clamp experiments on the squid giant axon. This included the identification of the major current responsible for the repolarization of the action potential, an outward potassium (K+) current activated by membrane depolarization. At that time, the size and complexity of the Kv channel gene family that we now know is responsible for voltage-dependent K+ currents could not have been imagined. A total of 40 genes encoding Kv channel α subunits have been identified in the human genome, and thus far, 10 of these have been directly associated with human diseases. The number of distinct Kv channels is further increased by alternative splicing and editing of the mRNA products of these Kv channel α subunit genes, by the ability of the α subunit polypeptides to combine in different homo- and hetero-tetrameric subunit configurations to form the functional Kv channels, and by the association of Kv channels with accessory subunits and other interacting proteins in native channel protein complexes. This results in a huge number of structurally distinct Kv channel complexes with unique biophysical and pharmacological properties, subcellular localization, and sensitivity to dynamic modulation by cellular signaling pathways. This diversity allows Kv channels to uniquely impact diverse aspects of electrical information processing. They shape neuronal firing properties, modulate neurotransmitter release, and influence dendritic signal processing. Moreover, the robust dynamic modulation of Kv channels by signaling pathways can impact their expression level, subcellular localization, and functional properties, which further enhances the diversity of this already complex family of ion channels. Kv channels therefore represent an inherently diverse toolbox for neurons to fine-tune their electrical properties, and the function of these cells and their circuits, and they also provide a rich substrate for dynamic modulation. In this chapter, we will review our current fundamental knowledge of this important, large, and diverse ion channel family.

Nomenclature of Kv Channels

Many of the 40 Kv channel α subunits, when originally identified, were assigned multiple names, making it somewhat difficult to navigate the early literature. However, based on a suggestion by Chandy, a systematic nomenclature for Kv channel α subunits was adopted by the International Union of Pharmacology (IUPHAR) (Chandy, 1991; Gutman et al., 2005), which was subsequently employed for other ion channels. The IUPHAR system has grouped the 40 human α subunits into 12 major subfamilies, Kv1–Kv12, based on sequence homology, the name “Kv” referring to a potassium channel (K) whose activation is voltage-dependent (v). In parallel, official names have been assigned to the α subunit genes by the HUGO Gene Nomenclature Committee (HGNC, http://www.genenames.org/cgi-bin/genefamilies/set/274). The genes are named KCN for K+ (K) channel (CN), followed by a letter characteristic of one, or in a few cases, several related subfamilies. In certain, but not all cases, the nomenclature of auxiliary subunits follows these conventions. Today most publications utilize the IUPHAR nomenclature when referring to the α and auxiliary subunit polypeptides, and the HGNC nomenclature for gene names. This systematic approach, which is summarized in Table 1, has greatly facilitated the unambiguous navigation of the scientific literature, albeit in the context of the somewhat intimidating genomic and proteomic complexity of the channels formed by this large gene family.

Table 1 Overview of Kv Channels: Naming, Subcellular Localization in Neurons, Basic Current Features, and Disease Associations

IUPHAR

HGNC

Predominant subcellular localization

Current characteristics

Associated human disease

Kv1 family

Kv1.1

KCNA1

AIS, juxtaparanodes, preterminal segment of axon

Fast, low activation threshold delayed rectifier

Episodic ataxia type 1

Kv1.2

KCNA2

AIS, juxtaparanodes, preterminal segment of axon

Fast, low activation threshold delayed rectifier

Early infantile epileptic encephalopathy-32

Kv1.3

KCNA3

Presynaptic (Calyx of Held)

Fast, low activation threshold delayed rectifier

Kv1.4

KCNA4

Preterminal segment of axon

Fast, low activation threshold A-current

Kv1.5

KCNA5

Mostly non-neuronal in brain

Fast, low activation threshold delayed rectifier

Kv1.6

KCNA6

Somatodendritic

Fast, low activation threshold delayed rectifier

Kv1.7

KCNA7

Fast, low activation threshold delayed rectifier

Kv1.8

KCNA10

Fast, low activation threshold delayed rectifier

Kv2 family

Kv2.1

KCNB1

Large clusters on soma, proximal dendrites, and AIS

Slow, high activation threshold delayed rectifier

Kv2.2

KCNB2

Large clusters on soma, proximal dendrites, and AIS

Slow, high activation threshold delayed rectifier

Kv3 family

Kv3.1

KCNC1

Presynaptic terminals, nodes of Ranvier

Fast, high activation threshold delayed rectifier

Kv3.2

KCNC2

Presynaptic terminals

Fast, high activation threshold delayed rectifier

Kv3.3

KCNC3

Presynaptic terminals

Fast, high activation threshold A-type current

Spinocerebellar ataxia type 13

Kv3.4

KCNC4

Presynaptic terminals

Fast, high activation threshold A-type current

Kv4 family

Kv4.1

KCND1

Somatodendritic

Fast, low activation threshold A-type current

Kv4.2

KCND2

Somatodendritic

Fast, low activation threshold A-type current

Kv4.3

KCND3

Somatodendritic

Fast, low activation threshold A-type current

Kv5 family

Kv5.1

KCNF1

Modifier of Kv2 currents

Kv6 family

Kv6.1

KCNG1

Modifier of Kv2 currents

Kv6.2

KCNG2

Modifier of Kv2 currents

Kv6.3

KCNG3

Modifier of Kv2 currents

Kv6.4

KCNG4

Modifier of Kv2 currents

Kv7 family

Kv7.1

KCNQ1

Slow, low activation threshold delayed rectifier

Long QT syndrome, Jervell Lange-Nielsen syndrome

Kv7.2

KCNQ2

AIS, nodes of Ranvier, presynapses

Slow, low activation threshold delayed rectifier

Benign familial neonatal epilepsy

Kv7.3

KCNQ3

AIS, nodes of Ranvier, presynapses

Slow, low activation threshold delayed rectifier

Benign familial neonatal epilepsy

Kv7.4

KCNQ4

Slow, low activation threshold delayed rectifier

Deafness, non-syndromic autosomal dominant 2

Kv7.5

KCNQ5

Possibly presynaptic

Slow, low activation threshold delayed rectifier

Kv8 family

Kv8.1

KCNV1

Modifier of Kv2 currents

Kv8.2

KCNV2

Inner segment of cone and rod photoreceptors of the retina

Modifier of Kv2 currents

cone-dystrophy with supernormal rod electroretinogram

Kv9 family

Kv9.1

KCNS1

Modifier of Kv2 currents

Kv9.2

KCNS2

Modifier of Kv2 currents

Kv9.3

KCNS3

Modifier of Kv2 currents

Kv10 family

Kv10.1

KCNH1

Presynaptic

Slow, low activation threshold delayed rectifier

Zimmermann-Laband and Temple-Baraitser syndromes

Kv10.2

KCNH5

Slow, low activation threshold delayed rectifier

Kv11 family

Kv11.1

KCNH2

Slow, low activation threshold delayed rectifier

Long QT syndrome

Kv11.2

KCNH6

Slow, low activation threshold delayed rectifier

Kv11.3

KCNH7

Slow, low activation threshold delayed rectifier

Kv12 family

Kv12.1

KCNH8

Slow, low activation threshold delayed rectifier

Kv12.2

KCNH3

Slow, low activation threshold delayed rectifier

Kv13.3

KCNH4

Slow, low activation threshold delayed rectifier

Faded channel subunits are not reported to have significant expression in neurons.

AIS: axon initial segment.

Cloning of Kv Channels

The first Kv channel α subunit was cloned by positional cloning in the Drosophila melanogaster Shaker mutant (Kamb, Iverson, & Tanouye, 1987; Papazian, Schwarz, Tempel, Jan, & Jan, 1987; Tempel, Papazian, Schwarz, Jan, & Jan, 1987). Within a year, the cDNA clone for the first mammalian Kv channel α subunit orthologue, appropriately named Kv1.1, was isolated from a mouse cDNA library by homology screening with Shaker cDNA probe (Tempel, Jan, & Jan, 1988). Over the next 12 years, the diversity of genes encoding Kv channel α subunits was uncovered, primarily through homology-based screening methods based on the high degree of sequence similarity within the core region comprising transmembrane segments S1–S6 (see the next section in this chapter), and employing low stringency hybridization techniques, reverse transcription-polymerase chain reaction (RT-PCR)based screening with degenerate primers or Basic Local Alignment Search Tool (BLAST) searches in the expressed sequence tag or genomic databases (reviewed in Vacher, Mohapatra, & Trimmer, 2008). Exceptions were the discoveries of the Kv2 and Kv7 subfamilies of Kv channel α subunits. A cDNA encoding Kv2.1 was isolated by functionally screening pools and then sub-pools of mRNAs generated from a rat brain cDNA library in Xenopus oocytes for Kv currents activated by membrane depolarization, ultimately leading to the isolation of a single clone, Kv2.1 (Frech, VanDongen, Schuster, Brown, & Joho, 1989). The human Kv7.1 α subunit gene was isolated by positional cloning and mutational analysis in an affected family due to its association with the inherited cardiac arrhythmia, long QT syndrome (Q. Wang et al., 1996).

Structure of Kv Channels

The polypeptides encoded by the 40 human Kv channel α subunit genes share several common structural characteristics. They all have a core domain of six transmembrane-spanning helices (S1–S6), a membrane-embedded P-loop connecting the S5 and S6 transmembrane segments, and cytoplasmic N- and C-terminal domains (Figure 1). A functional Kv channel is formed upon the assembly of four Kv channel α subunits (Long, Campbell, & MacKinnon, 2005; MacKinnon, 1991). The initial cloning of multiple isoforms of the Shaker α subunit suggested that Kv channel α subunits might assemble into both homo- and hetero-multimeric channel complexes, which turned out to be the case (see, e.g., Isacoff, Jan, & Jan, 1990; Ruppersberg et al., 1990). Indeed, the ability of Kv channel subunits to combine in different tetrameric subunit configurations greatly contributes to the variety of functional Kv channels expressed in neurons.

The structure of Kv channels.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 1 A. Schematic overview of the domain structure of a Kv channel α subunit. Each α subunit contains six transmembrane helical segments (S1–S6). S1–S4 make up the voltage-sensing domain (VSD), while S5–S6 and the connecting P-loop constitute the pore domain. The N- and C-terminal domains are cytoplasmic. “Extra” and “intra” refer to the extracellular and intracellular side of the PM, respectively. B. Ribbon representation of the crystal structure of Kv α subunits, in this case rat Kv1.2, illustrating the tetrameric assembly of Kv channels. Each subunit is labeled in a different color. “TM” refers to the transmembrane portion of the channel. C. The crystal structure of the Kv1.2 selectivity filter with the residues of the signature sequence (TVGYG) indicated on one side. For clarity, only two opposing α subunits are shown. The green dots represent the K+ ions in the four positions in the filter. Only two positions are in reality occupied at one time, with water molecules occupying the remaining two sites (2,4 and 1,3-configurations). Images B and C were created using Swiss-PDB Viewer and PDB ID: 3LUT.

The fundamental attributes of a Kv channel, to create a voltage-regulated passageway for K+ ions across the lipid bilayer, are encoded within the α subunit core domain comprising the S1–S6 transmembrane segments, which contains all of the transmembrane and extracellular domains of the α subunit as well as cytoplasmic linkers (Figure 1). The conductance passageway or pore is created by the assembly of the pore-forming domain, created by the S5 and S6 transmembrane segments and connecting P-loop present on each of the four α subunits, assembled in four-fold symmetry around the central pore (Figure 1). The resulting structure of the Kv channel pore domain (Long et al., 2005) is highly similar to the structure of KcsA, a K+ channel α subunit from Streptomyces lividans that has a simpler structure with only the two transmembrane segments and P-loop that forms the pore, and lacking the voltage-sensing domain present on Kv channels, and was the first K+ channel whose structure was solved at the atomic level (Doyle et al., 1998). The pore of these channels contains an inner water-filled cavity followed by a narrower selectivity filter (Figure 1). The selectivity filter is formed by the P-loop and contains a conserved signature sequence, TVGY(F)G, whose structure favors the coordination of dehydrated K+ ions since it mimics the water oxygens that surround hydrated K+ ions in solution. The open-channel pore creates an energetically favorable passageway for K+ ions that is extremely efficient as it allows conduction at near diffusion-limited rates (108 ions s–1) in a strongly K+ selective manner, such that in certain K+ channels, K+ ions are more than 10,000 times more permeant than sodium ions (Doyle et al., 1998; Morais-Cabral, Zhou, & MacKinnon, 2001). The voltage-sensing function of Kv channels primarily resides in the S1–S4 transmembrane segments, also known as the voltage-sensing domain (VSD), present in each α subunit and that in the Kv channel structure lie peripheral to the central pore (Figure 1). Importantly, the otherwise hydrophobic S4 transmembrane segment contains a positively charged amino acid residue at every third position, such that the S4 segment can sense and move in response to changes in membrane potential. The movements of the VSD are transferred to the pore domain either within the subunit (Whicher & MacKinnon, 2016) or between the VSD domain of one subunit and the pore-forming domain of the adjacent subunit, which is referred to as “domain-swapping” (Long et al., 2005). In either case, the transfer of movement between the VSD and the pore domain allows for voltage-dependent control of pore opening.

In contrast to the highly conserved S1–S6 core domain, the N-terminal cytoplasmic domain that precedes it and the C-terminal cytoplasmic domain that follows it differ considerably between the different Kv channel α subunits, and in particular between subunits from different Kv channel subfamilies. These cytoplasmic domains play diverse roles in dictating subfamily-specific subunit co-assembly, interaction with accessory subunits, and through their interaction with one another, they impact the voltage-dependent gating of the channel. Further, they serve as platforms for interaction with regulatory proteins that impact the function and subcellular localization of the Kv channel complex.

The Diversity of Kv Channels

Although the different members of the Kv channel family share many structural features, the ionic currents that arise from Kv channels formed by the co-assembly of different α subunits are remarkably different (Figure 2). Kv channels formed from α subunits from certain subfamilies respond to small membrane depolarizations (Kv1, Kv4, Kv7, Kv10–12), while those formed from others require the strong depolarization of the type obtained during action potentials to be activated (Kv2, Kv3). The rate with which this activation happens can also differ substantially between channels formed by the different α subunits. Kv channels formed from Kv1, Kv3, and Kv4 α subunits display fast activation kinetics, while those formed from Kv2, Kv7, and Kv10–12 α subunits activate more slowly. Finally, certain types of Kv channels inactivate while others conduct sustained currents, although this can be further impacted by co-assembly with certain auxiliary subunits. Four of the Kv α subunit subfamilies, namely Kv5, Kv6, Kv8, and Kv9, fail to produce currents when expressed alone in heterologous expression systems. These subfamilies are considered modulatory subunits for the Kv2 subfamily.

The diversity of Kv channels.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 2 A. A simplified overview of the biophysical properties of different Kv channels formed upon expression of the individual α subunits as indicated, and in which the various channels are arranged according to their voltage-dependent activation properties. B. Illustration of the primary subcellular localization(s) of different Kv channel α subunits. C. Confocal image of the axon initial segment (AIS) of a 17 days in vitro (DIV) cultured rat hippocampal neuron immunolabeled for the Kv1.1, Kv2.1, and Kv7.2 α subunits, illustrating their non-overlapping localizations within this specialized neuronal compartment.

In general, the different subfamilies of Kv channel α subunits preferentially localize to different neuronal sub-compartments (Figure 2). The Kv1 and Kv7 subfamilies are predominantly axonal channels, while Kv4 channels are exclusively localized to the somatodendritic region. Kv3 channels can be localized in either the axonal or the somatodendritic compartment, depending on the Kv3 subtype and the neuronal cell type. Kv2 channels are selectively found in the soma and proximal portions of both the axon and dendrites, but are noticeably absent in the distal regions of these processes. Even within these neuronal compartments, different Kv channel α subunits display further compartmentalization. For instance, α subunits from the Kv1, Kv2, and Kv7 subfamilies are all present at the axon initial segment (AIS), the site of action potential initiation (Figure 2). However, each Kv subfamily member has its own unique localization within this compartment, resulting in an impressive mosaic of Kv channel localization patterns when the members of these three subfamilies are visualized in the same cell (Figure 2).

The 40 different Kv channel α subunits encoded in mammalian genomes are thus endowed with distinct functional characteristics as well as distinct cellular and subcellular expression patterns. This allows them to regulate different aspects of neuronal information processing and also to be subjected to modulation by distinct local signaling events. The cellular expression patterns of distinct Kv channel α subunits in different neuronal cell types yield distinct repertoires of homo- and hetero-tetrameric Kv channel complexes localized at specific subcellular sites, and a diversity of expression, function, and regulation that greatly contributes to defining the specific firing properties and shaping of other functions of individual neurons. While the Kv1, Kv2, Kv3, Kv4, and Kv7 subfamilies have been extensively studied, and relatively more is known in terms of their expression, subcellular localization, and contributions to neuronal functions, relatively little is known when it comes to the electrically silent Kv channels as well as the Kv10–Kv12 subfamilies. These latter Kv channels comprise a substantial component of what is currently regarded as the under-studied druggable genome (https://commonfund.nih.gov/idg).

The Kv1 Subfamily

The members of the Kv1 channel subfamily are orthologues of the Drosophila Shaker channel and are sometimes referred to as the Shaker subfamily. They constitute the largest single Kv channel α subunit subfamily, with eight members named Kv1.1–1.8 (Table 1). Of these, Kv1.1–Kv1.6 are expressed in brain, with Kv1.1, Kv1.2, and Kv1.4 being the most prominently expressed subunits (reviewed in Vacher et al., 2008). Kv1 channel α subunits contain a large cytoplasmic N-terminus and a relatively smaller C-terminal domain (Figure 3). Upon expression in heterologous expression systems, Kv1 α subunits give rise to low-voltage activated K+ currents that activate with fast activation kinetics (Figure 3). The exact activation threshold and activation kinetics differ among homo- and hetero-tetrameric channels made from different Kv1 α subunits, with homo-tetrameric Kv1.1 channels displaying the lowest activation threshold and the fastest activation kinetics (reviewed in Ovsepian et al., 2016). Homo-tetrameric channels formed from most Kv1 subfamily members display little or no inactivation, resulting in sustained delayed rectifier-type K+ currents, with the clear exception of Kv1.4, which produces transient A-type currents due to a pronounced N-type inactivation (Figure 3). Although homo-tetrameric Kv1 channels are produced in heterologous expression systems and are also found to some extent in brain neurons, most neuronal Kv1 channels are hetero-tetramers of two or more distinct α subunit in vivo (Coleman, Newcombe, Pryke, & Dolly, 1999). The subfamily-specific assembly of Kv1 channel α subunits into homo- or hetero-tetramers depends on an N-terminal T1 tetramerization domain that allows Kv1 subunits to assemble with other members of the Kv1 subfamily, but not with those of other Kv subfamilies (Figure 3; Li, Jan, & Jan, 1992). Hetero-tetrameric Kv1 channels display biophysical and pharmacological properties, as well as trafficking properties (Manganas & Trimmer, 2000) that are shaped by the contributing channel α subunits, thereby creating further diversity in neuronal Kv1 currents (Coleman et al., 1999).

The Kv1 subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 3 A. Schematic overview of the domain structure of a Kv1 α subunit. The associated cytoplasmic Kvβ auxiliary subunit is included. B. Left side: Representative current trances obtained in Xenopus laevis oocytes expressing Kv1.1, Kv1.1 in combination with Kvβ1.1 or Kv1.4. Current traces were recorded by applying depolarizing potentials from –60 to +50 mV with a 10 mV increment for 200 ms from a holding potential at –80 mV. Right side: Representative whole-cell current traces for Kv1.4 transiently expressed in CHO-K1 cells. Currents were evoked by step depolarization to test potentials between −90 and +70 mV for 500 ms in 20 mV increments. (Adapted with permission from Fan, Bi, Jin, & Qi, 2010; Jow, Zhang, Kopsco, Carroll, & Wang, 2004.) C. Ribbon representation of the crystal structure of the rat Kv1.2 α subunit in complex with rat Kvβ2 (PDB ID: 3LUT). Kv1.2 is shown in red except for the T1 domain, which is orange. Kvβ2 is represented in cyan. (Image created with Swiss-PDB Viewer.) D. Confocal image of a 17 DIV cultured rat hippocampal neuron immunolabeled for the Kv1.1 α subunit and the somatodendritic marker microtubule associated protein 2 (MAP2), illustrating primarily axonal localization of this α subunit. E. Kv1.2 localization in paranodes in sciatic nerve axons. Kv1.2 is expressed in the juxtaparanodal regions that surround the node of Ranvier (labeled for voltage-gated sodium channels in green) and paranodes (labeled for Caspr in blue). (Adapted with permission from Horresh et al., 2008; Jensen, Rasmussen, & Misonou, 2011.) F. Kv1.2 localization at the axon initial segment (AIS) of rat layer 5 pyramidal cells (L5PC). The localization of the AIS was visualized by immunolabeling for Nav1.6. “So” indicates the location of the soma. (Adapted with permission from Lorincz & Nusser, 2008.)

Kv1 Accessory Proteins

The N-terminal T1 domain also serves as a docking site for the regulatory Kvβ auxiliary subunits (Figure 3). These are cytoplasmic oxidoreductase proteins that co-assemble with and regulate the biophysical properties and intracellular trafficking of Kv1 channels. The critical role of Kvβ subunits in Kv1 channel function has been revealed by loss-of-function mutations in Kvβ subunits that phenocopy mutants lacking Kv1 expression (Chouinard, Wilson, Schlimgen, & Ganetzky, 1995; Heilstedt et al., 2001). The binding of Kvβ subunits to the T1 domain has been elegantly demonstrated by crystal structures of both the isolated T1 domain as well as full-length Kv1.2 in association with Kvβs. The crystal structures have revealed that the T1 tetramer is separated from the intracellular pore opening as a “hanging gondola,” with the Kvβ subunits attached to its lower side (Figure 3; Kobertz, Williams, & Miller, 2000; Long et al., 2005). In mammals, three Kvβ subunit genes have been identified—Kvβ1–3—and transcripts from each are subject to alternative splicing. The Kvβ subunits exert distinct effects on the biophysical properties of Kv1 channels (reviewed in Pongs & Schwarz, 2010). The most well-described effect is that of Kvβ1.1, which confers rapid N-type inactivation to Kv1 channels that would otherwise lack it due to the presence of an N-terminal inactivation peptide on Kvβ1.1 that blocks the open channel pore (Figure 3; Pongs & Schwarz, 2010). A similar mechanism causes the rapid inactivation in Kv1.4-containing channels, as the extended N-terminus of the Kv1.4 α subunit contains a similar inactivation peptide (Figure 3). The physiological role of the oxidoreductase activity of the Kvβ subunits remains unclear, though there appears to be a coupling between the oxidoreductase activity and the Kv1 current modulation by Kvβ subunits (Pongs & Schwarz, 2010).

Kv1 channels have also been found associated with the leucine-rich glioma-inactivated 1 (LGI1) protein, a secreted neuronal protein that is linked to autosomal-dominant lateral temporal lobe epilepsy (Schulte et al., 2006). LGI1 regulates both inactivation kinetics and expression levels of Kv1 channels, resulting in increased current levels (Schulte et al., 2006; Seagar et al., 2017). While the mechanism by which LGI1 regulates Kv1 channels remains obscure, LGI1 is a ligand for the catalytically inactive metalloprotease ADAM22, another component of the Kv1 complex (Fukata et al., 2006; Ogawa et al., 2010; Schulte et al., 2006; Yamagata et al., 2018). Intriguingly, individually knocking out Lgi1, Adam22, Kv1.1, Kv1.2, and Kvβ2 leads to an epileptic phenotype in mice, potentially supportive of a functional link between these proteins present in native brain Kv1 channel complexes (Brew et al., 2007; Connor et al., 2005; Fukata et al., 2006; Sagane et al., 2005; Smart et al., 1998).

Kv1 Subcellular Localization

Kv1 channels are predominantly axonal channels, with the exception of those containing Kv1.6 that are somatodendritic (reviewed in Vacher et al., 2008). The axonal Kv1 channels localize to the AIS, the juxtaparanode, and the preterminal segment of the axon (Figure 3). The localization appears to involve Kvβ subunits that promote axonal localization of Kv1 channels upon heterologous expression in cultured hippocampal neurons (Campomanes et al., 2002; Gu, Jan, & Jan, 2003). However, the localization of the Kv1.1 and Kv1.2 α subunits is unaffected in Kvβ2 and Kvβ1.1/Kvβ2 double knockout mice, suggesting that the Kvβ subunits that are abundantly associated with these Kv1 α subunits in brain (Rhodes et al., 1997) are not absolutely required for their axonal localization, a conundrum that remains to be solved (Connor et al., 2005; McCormack et al., 2002). In their extreme C-terminus, Kv1 α subunits contain a post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ)-binding motif that interacts with members of the membrane-associated guanylate kinase (MAGUK) family (Figure 3; Kim, Niethammer, Rothschild, Jan, & Sheng, 1995), and MAGUKs co-purify with Kv1.1 from rat brain (Schulte et al., 2006). However, the role of MAGUKs in the localization of Kv1 channels remains obscure as axonal Kv1 channels are normally clustered in both PSD-93 and PSD-95 knockout mice (Ogawa et al., 2010; Rasband et al., 2002).

Kv1 Function in Neurons

Due to a combination of their fast, low-threshold activation and their subcellular localization, Kv1 channels significantly impact the axonal action potential by regulating its threshold, waveform, and frequency (see, e.g., Johnston, Forsythe, & Kopp-Scheinpflug, 2010; Kole, Letzkus, & Stuart, 2007). They further regulate the release of neurotransmitter from presynaptic terminals (see Yang et al., 2014). Here, inactivating Kv1 currents display cumulative inactivation during trains of action potentials, which leads to a broadening of the presynaptic action potential, increased calcium influx, and potentiation of neurotransmitter release (reviewed in Dodson & Forsythe, 2004). Mutations in the Kv1.1 gene KCNA1 are associated with inherited episodic ataxia type 1 (EA1; Rajakulendran, Schorge, Kullmann, & Hanna, 2007), and de novo mutations in the Kv1.2 gene KCNA2 with early infantile epileptic encephalopathy-32 (EIEE32; Pena & Coimbra, 2015).

The Kv2 Subfamily

The Kv2 subfamily consists of two members named Kv2.1 and Kv2.2, which are orthologues of the Drosophila Shab channel (Table 1). The Kv2 α subunits are broadly and robustly expressed in the nervous system, with Kv2.1 having the broadest expression (Trimmer, 2015). They are equipped with a long N-terminal domain and an extremely long C-terminus (Figure 4). When expressed in heterologous expression systems, the channels form sustained delayed rectifier-type currents that activate with slowactivation kinetics (Figure 4). Though the formation of Kv2.1/Kv2.2 heteromers is possible (Kihira, Hermanstyne, & Misonou, 2010), the overall extent to which this happens in vivo is not clear (Bishop et al., 2015). Kv2 α subunits can co-assemble with members of the electrically silent Kv5, Kv6, Kv8, and Kv9 subfamilies, which leads to altered biophysical properties of Kv2-mediated K+ currents (see section on KvS subunits, this chapter). Again, the extent to which this heteromerization takes place in vivo is unclear, as most studies are based on heterologous expression (Bocksteins, 2016). As in Kv1 channels, the specific assembly of α subunits within the Kv2 subfamily, and with Kv5, Kv6, Kv8, and Kv9 α subunits, is regulated by an N-terminal T1 tetramerization domain (Figure 4). Electron microscopy and single-particle image analysis have revealed that the Kv2.1 T1 domain is almost completely surrounded by the long Kv2.1 C-terminus that wraps around it and occupies the space below it (Figure 4; Adair et al., 2008; Grizel et al., 2014).

The Kv2 subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 4 A. Schematic overview of the domain structure of a Kv2 α subunit. The associated single-pass transmembrane cell adhesion molecule AMIGO-1 is included. AIS: axon initial segment, PRC: proximal restriction and clustering. B. Representative whole-cell current traces from HEK293 expressing the Kv2.1 α subunit. The cells were held at –100 mV and step depolarized to +80 mV for 200 ms in 10 mV increments. C. Voltage-dependent activation (squares) and steady-state inactivation (circles) relationships of Kv2.1 currents in HEK293 cells before (filled symbols) and after (open symbols) dephosphorylation induced by intracellular dialysis of alkaline phosphatase for 30 minutes, illustrating the hyperpolarized shift in the dephosphorylated channels. Error bars represent mean ± standard error of the mean (SEM). (B and C were adapted from Mohapatra & Trimmer, 2006.) D. Surface-shaded 3D density map of human Kv2.1 at ≈25 Å resolution. The location of the C-terminus is indicated by the black line. “TM” refers to the transmembrane portion of the channel. (Adapted with permission from Adair et al., 2008.) E. Confocal image of a 17 DIV cultured rat hippocampal neuron immunolabeled for the Kv2.1 α subunit and MAP2, illustrating the clustered localization of Kv2.1 on the soma and proximal dendrites and AIS. F. Localization of Kv2.1 (green), Kv2.2 (red), and the accessory protein AMIGO-1 (blue) in mouse somatosensory cortical neurons, illustrating the highly clustered Kv2 localization on soma and proximal neurites. Different pyramidal cells of the cortex express different levels of Kv2.1 and Kv2.2, as demonstrated in the inserts to the right (F1–F6). (Adapted from Bishop et al., 2018.)

Kv2 Accessory Proteins

Kv2 channels interact and co-localize extensively with amphoterin-induced gene and ORF 1 (AMIGO-1), a single-pass transmembrane cell adhesion molecule that can also act to promote neurite outgrowth (Figure 4; Bishop et al., 2018; Mandikian et al., 2014; Peltola, Kuja-Panula, Lauri, Taira, & Rauvala, 2011). AMIGO-1 appears to be an integral component of both Kv2.1- and Kv2.2-containing channel complexes in adult brain neurons, as it exhibits an almost complete overlap in cellular and subcellular localization with Kv2 channels, and it depends on Kv2 α subunits for its proper expression and subcellular localization (Bishop et al., 2018; Mandikian et al., 2014; Peltola et al., 2011). It is tempting to speculate that, given its established role as a cell adhesion molecule, AMIGO-1 could be involved in the localization of neuronal Kv2 clusters at contact sites for astrocytic processes (see section on Kv2 subcellular localization, next).

Kv2 Subcellular Localization

The subcellular localization of Kv2 channels beautifully illustrates that, while ion channels are often localized to pre-established membrane domains, they can also impact and even generate the molecular and structural organization of the domains at which they are found. Kv2 channels exhibit a unique, highly restricted subcellular localization in neurons, where they are localized at high density in large clusters restricted to the soma, the proximal segment of the dendrites, and the AIS (Figure 4). Kv2 clusters are located at endoplasmic reticulum (ER)–plasma membrane (PM) or ER-PM junctions, termed “subsurface cisternae” in neurons, and are juxtaposed to astrocytic processes (Bishop et al., 2015; Du, Tao-Cheng, Zerfas, & McBain, 1998; Fox et al., 2015; Misonou, Thompson, & Cai, 2008). This specific localization is due to a Kv2-specific motif localized in the extended C-terminal domain, the proximal restriction and clustering (PRC) motif that is present in both the Kv2.1 and Kv2.2 α subunits (Figure 4; Bishop et al., 2015; Lim, Antonucci, Scannevin, & Trimmer, 2000). The motif interacts with ER-resident vesicle-associated membrane-associated proteins isoform A and B (VAPA and VAPB) and this interaction probably drives the clustering of Kv2.1 and Kv2.2 as well as organizes the ER-PM junctions themselves (Johnson et al., 2018; Kirmiz, Palacio, et al., 2018; Kirmiz, Vierra, Palacio, & Trimmer, 2018). The remodeling of ER-PM junctions via interaction with VAP proteins is retained in Kv2.1 and Kv2.2 mutants lacking ionic conductance, showing that it is a bona fide non-conducting function of Kv2 channels (Kirmiz, Palacio, et al., 2018). This is especially intriguing as the bulk of exogenously expressed Kv2.1 channels are in a non-conducting state (Benndorf, Koopmann, Lorra, & Pongs, 1994; Fox, Loftus, & Tamkun, 2013; K. M. S. O’Connell, Loftus, & Tamkun, 2010). While the Kv2-specific PRC motif supports localization to the AIS and also clusters VAPA/VAPB at this location, Kv2.1 has an additional motif in the C-terminus, the AIS motif, which also contributes to its clustered localization in this subcellular compartment by acting as a motif for directing its non-canonical trafficking to the AIS (Figure 4, Jensen et al., 2017). How this motif mediates Kv2 channel clustering remains unknown, but it could be though binding to another ER resident protein specific to the AIS. Intriguingly, the AIS motif is not well conserved in Kv2.2, which suggests that its localization on the AIS could have a distinct underlying mechanism. The clustered localization of Kv2 channels is dynamically regulated such that increasing neuronal activity causes dispersion of Kv2 clusters and retraction of the subsurface cisternae from the PM, most likely caused by a disruption of the interaction between Kv2s and VAPs (Fox et al., 2015; Kirmiz, Vierra, et al., 2018; Misonou et al., 2004). The dispersion is associated with and probably driven by dephosphorylation of Kv2.1, and is associated with a hyperpolarizing shift in the voltage-dependence of activation (Figure 4; Misonou et al., 2004; Murakoshi, Shi, Scannevin, & Trimmer, 1997). Kv2.1 is more responsive to these activity-dependent changes in subcellular localization and voltage activation than is Kv2.2 (Bishop et al., 2015).

Kv2 Function in Neurons

In accordance with their high expression levels, Kv2 channels constitute the major part of somatic delayed rectifier-type K+ current in many neuronal cell types (Du, Haak, Phillips-Tansey, Russell, & McBain, 2000; Guan, Tkatch, Surmeier, Armstrong, & Foehring, 2007; Liu & Bean, 2014; Malin & Nerbonne, 2002; Murakoshi & Trimmer, 1999; Palacio et al., 2017). As Kv2 channels activate with slow kinetics, they have their most significant impact during periods of repetitive firing, where they can facilitate high frequency-firing, but also limit dendritic calcium transients (Du et al., 2000; Guan, Armstrong, & Foehring, 2013; J. Johnston et al., 2008; Liu & Bean, 2014). Further, when neuronal activity levels are high, the resulting hyperpolarized activation of Kv2.1 results in a suppression of excitability (Mohapatra et al., 2009). Due to their subcellular localization, high expression level, and activity-dependent regulation, Kv2 channels are thus key regulators of intrinsic excitability. In support of this, Kv2.1 knockout mice display neuronal and behavioral hyperexcitability (Speca et al., 2014). A number of recent studies have found de novo mutations in the KCNB1 gene encoding Kv2.1 associated with pediatric encephalopathic epilepsy patients (Saitsu et al., 2015; Thiffault et al., 2015; Torkamani et al., 2014).

The Kv3 Subfamily

Kv3 α subunits are mammalian orthologues of the Drosophila Shaw gene products. The Kv3 α subunit subfamily includes four members, Kv3.1–Kv3.4, all of which are expressed in the nervous system (Table 1). These α subunits contain a large N-terminus and a C-terminal domain of variable length, with Kv3.3 having the longest C-terminus (Figure 5). Due to extensive alternative mRNA splicing, Kv3 subfamily members are present in multiple isoforms that differ in the length and sequence of the C-terminal domain (for review, see Kaczmarek & Zhang, 2017). When expressed in heterologous cells, Kv3 α subunits can generate non-inactivating delayed rectifier-type currents (Kv3.1 and Kv3.2) or A-type currents (Kv3.3 and Kv3.4) (Figure 5). Kv3-mediated currents are characterized by a high activation threshold and very fast activation and deactivation kinetics. The inactivation observed in Kv3.3 and Kv3.4 α subunits is due to the presence of an N-terminal inactivation peptide in these α subunits (Figure 5) similar to the mechanism observed in Kv1.4. Kv3 α subunits can form hetero-tetrameric channels, a process regulated by the N-terminal T1 tetramerization domain (Figure 5).

The Kv3 subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 5 A. Schematic overview of the domain structure of a Kv3 α subunit. B. Representative Kv3 currents in transfected Chinese hamster ovary (CHO) cells, illustrating the different kinetics of inactivation for the different isoforms. The cells were subjected to depolarizing pulses from −40 mV to +40 mV (in 10 mV increments, from a holding potential of −80 mV). C. Normalized conductance–voltage relationship of Kv3 currents expressed in CHO cells. The conductance at the indicated voltage [g= IV/(V-VK)], divided by the maximum conductance (gmax) for the currents shown in A, is plotted as a function of membrane potential. (A and B were adapted with permission from Rudy & McBain, 2001.) D. Immunolocalization of the Kv3.1b α subunit in nodes of Ranvier of the spinal cord. The juxtaparanodes were immunolabeled with a Kv1.2 antibody, demonstrating the compartmentalized localization of the two Kv channels in this axonal subdomain. (Adapted with permission from J. Devaux et al., 2003.)

Kv3 Accessory Proteins

The C-terminus of Kv3.3 binds the cell survival protein Hax-1, which activates Arp2/3-dependent formation of a cortical actin filament network just below the PM (Zhang et al., 2016). The presence of the cortical actin cytoskeleton slows channel inactivation and is most likely the explanation for the different rates of inactivation observed between Kv3.3 and Kv3.4. The modulation of the submembranous actin organization exerted by Kv3.3 through its interaction partner Hax-1 is another beautiful demonstration of the impact ion channels can have on the structure and molecular organization of the domains in which they are embedded. We will most likely encounter many more of these alternative actions of ion channels in the future.

Kv3 Subcellular Localization

Kv3 channels can be localized to both the axonal and somatodendritic domains. Most often, they are localized to the soma, proximal dendrites, nodes of Ranvier, and presynapses (Figure 5). The localization varies with the neuronal cell type, even for the same Kv3 isoform (reviewed in Vacher et al., 2008). Axonal targeting appears to involve conditional binding to the scaffold protein ankyrin-G (ankG) through an axonal targeting motif present in the proximal C-terminal tail of all Kv3 subfamily members (Figure 5; Xu, Cao, Xiao, Zhu, & Gu, 2007). Kv3 targeting to distal dendrites appears to involve a potential PDZ-binding motif present at the extreme C-terminus of some Kv3 isoforms (Figure 5; Deng et al., 2005).

Kv3 Function in Neurons

Since Kv3 channels are characterized by a high activation threshold, they are only activated during action potentials, and due to their fast activation kinetics, they contribute substantially to membrane repolarization. In Kv3-expressing neurons, loss of Kv3 current broadens the action potential and eliminates the afterhyperpolarization, which impairs the ability of neurons to fire at high frequencies due to accumulated inactivation of Nav channels (reviewed in Kaczmarek & Zhang, 2017). Accordingly, Kv3 α subunits are robustly expressed in fast-spiking neurons such as auditory brain stem neurons, parvalbumin-positive GABAergic interneurons, and Purkinje cells of the cerebellum (Trimmer, 2015). In addition to their critical role in permitting high-frequency firing, Kv3 channels present at presynaptic terminals are important regulators of synaptic efficacy, with inhibition of Kv3 current resulting in a broadening of the action potential, increased presynaptic calcium influx, and enhanced neurotransmitter release (reviewed in Kaczmarek & Zhang, 2017). Certain inherited mutations in the KCNC3 gene that encodes Kv3.3 cause neurodegenerative spinocerebellar ataxia type 13 (SCA13; Waters et al., 2006).

The Kv4 Subfamily

The Kv4 subfamily consists of α subunits that are orthologues of the Drosophila Shal gene product. The Kv4 subfamily contains three members, Kv4.1–4.3, all of which are expressed in the nervous system with Kv4.2 and Kv4.3 being the most predominantly expressed α subunits (Table 1). Kv4 α subunits contain large N- and C-terminal domains (Figure 6). Kv4 channels generate low threshold, fast activating and inactivating A-type currents upon heterologous expression (Figure 6). The fast inactivation is of the N-type and can be mediated by the N-terminus of the α subunit itself, or by the N-terminus of the accessory dipeptidyl peptidase-like (DPPL) α subunits (Figure 6; Jerng & Pfaffinger, 2014). Kv4 currents are furthermore unique in that they are typically inactivated at resting membrane potentials and require a prior hyperpolarization to activate. This is due to a closed state inactivation that requires hyperpolarized membrane potentials to recover (Jerng & Pfaffinger, 2014). Heteromeric assembly between different Kv4 channel α subunits is possible and is dictated by an N-terminal T1 tetramerization domain (Figure 6).

The Kv4 subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 6 A. Schematic overview of the domain structure of a Kv4 α subunit. The cytoplasmic Kv channel-interacting protein (KChIP) as well as the single-pass transmembrane dipeptidyl peptidase-like (DPPL) auxiliary subunits are included. B. Representative current trances obtained in Xenopus laevis oocytes expressing Kv4.2 alone or in combination with KChIP3 and DPP10a as indicated. Currents were elicited by 1-second-long depolarizing pulses from −100 to +60 mV in 10 mV increments from a holding potential of −100 mV. Only the first 250 ms are shown. (Adapted with permission from Jerng, Lauver, & Pfaffinger, 2007.) C. Ribbon representation of the crystal structure of the isolated N-terminus of the human Kv4.3 α subunit in complex with KChIP1. The Kv4.3 N-terminus is represented in yellow and KChIP in cyan. The image was created with Swiss-PDB Viewer and PDB ID: 2NZ0. D. Cultured rat hippocampal neuron immunolabeled for the Kv4.2 α subunit, illustrating its expression on the soma and dendrites. The localization of dendritic spines that can also contain Kv4.2 was visualized by immunolabeling for PSD-95. (Figure adapted with permission from C. S. Jensen et al., 2011.) E. Confocal image from rat substantia nigra illustrating the somatodendritic localization of Kv4.3 α subunits in dopaminergic neurons. “TH” is tyrosine hydroxylase, a marker of dopaminergic neurons.

Kv4 Accessory Proteins

Kv4 members interact with and are modulated by the cytoplasmic, calcium-binding proteins known as Kv channel-interacting proteins (Figure 6, KChIPs; An et al., 2000). Due to a number of start sites and alternative splicing, the four members of this subfamily, KChIP1–4, exist in an impressive 17 isoforms with distinct expression patterns in brain (reviewed in Jerng & Pfaffinger, 2014). KChIPs interact with Kv4 channels through a hydrophobic sequence located in the extreme N-terminus of one channel α subunit and the T1 domain of the adjacent α subunit, thereby clamping them (Pioletti, Findeisen, Hura, & Minor, 2006; Scannevin et al., 2004; H. Wang et al., 2007). Crystal structures of the isolated Kv4.3 N-terminus in association with KChIP1 reveal that the KChIP subunits are located lateral to the T1 domain, in contrast to the Kvβ subunits that are placed below the T1 domain of Kv1 α subunits (Figure 6). In general, KChIPs promote surface-expression of Kv4 channels (Shibata et al., 2003), slow N-type inactivation, and accelerate recovery from inactivation (Figure 6; reviewed in Jerng & Pfaffinger, 2014). That one of the primary functions of KChIPs is to regulate Kv4 function is supported by the observation that KChIP protein levels are drastically reduced in Kv4.2 knockout mice (Menegola & Trimmer, 2006), probably due to destabilization of the KChIPs in the absence of their Kv4 binding partners (Foeger, Marionneau, & Nerbonne, 2010).

Two DPPLs named DPP6 and DPP10 also interact with and critically regulate Kv4 channels (Figure 6; Nadal et al., 2003; Zagha et al., 2005). Like KChIPs, they exist in various isoforms. DPPLs are single-pass transmembrane proteins that profoundly impact the biophysical properties of Kv4 channels by shifting both activation and inactivation in the hyperpolarized direction, accelerating inactivation and altering channel conductance (Figure 6; reviewed in Jerng & Pfaffinger, 2014). DPPLs interact with the Kv4 VSD, which possibly explains the strong impact of these subunits on channel activation (Dougherty, Tu, Deutsch, & Covarrubias, 2009). Like KChIPs, DPPLs promote surface expression of Kv4 channels (Foeger, Norris, Wren, & Nerbonne, 2012; Seikel & Trimmer, 2009). DDP6 knockout mice show significant reductions in both Kv4 and KChIP expression, suggesting that DPPLs are critical regulators of the overall stability of Kv4 complexes (Sun et al., 2011). While DPP6 is generally expressed in neurons that also express Kv4.2, DPP10 shows significant co-expression with Kv4.3 (Clark et al., 2008; Nadal, Amarillo, Vega-Saenz de Miera, & Rudy, 2006; Zagha et al., 2005). That selective co-expression patterns also hold for KChIPs (Rhodes et al., 2004) that can form a ternary complex with Kv4 α subunits and DPPLs (Jerng, Kunjilwar, & Pfaffinger, 2005) suggests a preferential association between certain Kv4 α and auxiliary subunits to impact the characteristics of Kv4 channels.

Kv4 Subcellular Localization

Kv4 channels are exclusively expressed in the somatodendritic compartment (Figure 6; Kerti, Lorincz, & Nusser, 2012; Rhodes et al., 2004), and functional Kv4 channels are found with an increasing gradient of expression towards the distal dendrites (Hoffman, Magee, Colbert, & Johnston, 1997). The somatodendritic gradient is lost in DPP6 knockout mice, demonstrating a critical role of this accessory subunit in establishing the gradient (Sun et al., 2011). The somatodendritic localization furthermore requires a dileucine motif present in the cytoplasmic C-terminal tail (Figure 6; Rivera, Ahmad, Quick, Liman, & Arnold, 2003). How this motif mechanistically confers somatodendritic localization remains unclear, but its mutation in Kv4.2 impacts the post-Golgi vesicular trafficking of the channel, suggesting a possible role in vesicular sorting (Jensen et al., 2014). Kv4 channels also contain a C-terminal PDZ-binding motif, and while the motif can mediate interaction with PSD-95, its exact function is currently not clear (Wong, Newell, Jugloff, Jones, & Schlichter, 2002).

Kv4 function in Neurons

Kv4 channels in complex with KChIP and DPPL subunits underlie the subthreshold A-type transient current (ISA) observed in the somatodendritic compartment of most neurons (Jerng & Pfaffinger, 2014). The most striking feature of this current is its impact on dendritic signal processing. Due to its localization and low threshold, rapid activation, the ISA current plays an important role in dampening the back-propagation of action potentials into dendrites (Hoffman et al., 1997). However, since Kv4 channels require hyperpolarization to recover from inactivation, Kv4 currents are selectively suppressed in dendrites that have experienced recent depolarizing activity. These dendrites experience larger back-propagating action potentials and increased calcium influx, which contribute to the compartmentalized regulation of long-term potentiation of excitatory synaptic transmission (LTP) (Johnston et al., 2003). In accordance, hippocampal CA1 neurons of Kv4.2 knockout mice display an increase in the amplitude of back-propagating action potentials, associated elevations in dendritic calcium influx, and altered LTP induction (Chen et al., 2006).

The Kv7 Subfamily

The Kv7 α subunits were initially referred to by their gene name KCNQ, and even today some publications utilize this name. The subfamily contains five members named Kv7.1–7.5, and all except Kv7.1 display neuronal expression (Table 1). The most prominent neuronal α subunits are Kv7.2, Kv7.3, and Kv7.5, as Kv7.4 displays a very restricted expression: only being present in certain auditory nuclei (Kharkovets et al., 2000). While the N-terminus in Kv7 channels is shorter than in most other Kv subfamilies, they contain extremely long C-terminal domains that make up around half the protein (Figure 7). In heterologous expression systems, channels formed upon expression of Kv7 α subunits generate low-threshold, slowly activating delayed rectifier-type currents that display little or no inactivation (Figure 7). The channels require binding of the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) for channel opening, and its depletion results in the inhibition of the current, most likely due to an uncoupling between the VSD and the pore domain (Suh & Hille, 2002; Sun & MacKinnon, 2017; Zaydman & Cui, 2014). Hetero-tetramerization within this subfamily is extensive, with the most commonly observed neuronal Kv7 channels most likely being Kv7.2/Kv7.3 heteromers (Hadley et al., 2003). The Kv7 α subunits do not contain the conserved N-terminal T1 assembly domain observed in most other Kv channel α subunits. Instead, tetramerization is regulated by two C-terminal coiled-coil regions, helices C and D (Figure 7; Schwake et al., 2006). While helix C is required for the tetramerization, helix D appears to regulate the subtype-specific heteromerization.

The Kv7 subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 7 A. Schematic overview of the domain structure of a Kv7 α subunit. The associated regulatory calmodulin (CaM) subunit is included. B. Representative current trances obtained in Xenopus laevis oocytes expressing Kv7.5 alone, Kv7.2 and Kv7.3, or Kv7.3 and Kv7.5, as indicated. Currents were activated by voltage-steps from −80 mV to +40 mV in 10 mV increments. (Adapted from Gilling et al., 2013.) C. Ribbon representation of the cryoEM structure of Xenopus Kv7.1 in complex with CaM. Kv7.1 is shown in red except for helices A and B, which are shown in green, and helix C, which is represented in orange. One CaM molecule is shown in purple. For better visualization, the other three CaM molecules are colored gray. The image was created with Swiss-PDB Viewer and PDB ID: 5VMS. D. Confocal image of a 17 DIV cultured rat hippocampal neuron immunolabeled for the Kv7.2 α subunit and betaIV-spectrin (a marker of the AIS), illustrating the primarily axonal localization of Kv7.2. E. High-magnification image of a larger node of Ranvier within the L5 somatosensory cortex. Kv7.2 antibodies immunolabel the nodal membrane, which is flanked by Caspr at the paranodes. F. Maximal projection image of a large L5 somatosensory neuron co-labeled for the Kv7.2 α subunit and the AIS marker ankG, illustrating the localization of this α subunit in the distal AIS. (E and F were adapted with permission from Battefeld, Tran, Gavrilis, Cooper, & Kole, 2014.)

Kv7 Accessory Proteins

The proximal Kv7 C-terminal tail contains two other helical structures, helices A and B, which bind the calcium-binding protein calmodulin (CaM; Figure 7; Wen & Levitan, 2002; Yus-Najera, Santana-Castro, & Villarroel, 2002). CaM appears to be an integral part of the Kv7 channel complex, as Kv7 channels interact with both the calcium-free Apo/CaM as well as the calcium-loaded CaM form. Crystal structures of helices A and B in complex with CaM reveal that CaM clamps the proximal C-terminal tail in the absence of calcium, a clamp that is released upon calcium binding, leading to inhibition of voltage-dependent activation of the neuronal Kv7 channels (Figure 7; Chang et al., 2018; Gamper & Shapiro, 2003). Interestingly, Apo/CaM binding also appears to be essential for efficient cell surface expression of Kv7 channels, most likely by promoting exit from the ER (Cavaretta et al., 2014; Chang et al., 2018; Etxeberria et al., 2008). This suggests that only the Kv7 channels that are equipped with the machinery for the proper calcium-dependent regulation of their activity are allowed to traffic to the cell surface. The presence of CaM on ER-localized Kv7 channels raises the possibility that their exit from the ER can be modulated by intracellular calcium levels.

Kv7 Subcellular Localization

The Kv7 channels are predominantly axonal channels with localizations to the AIS, nodes of Ranvier, and presynapses (Figure 7; Devaux, Kleopa, Cooper, & Scherer, 2004; Vacher et al., 2008). Localization to the AIS requires a sequence in the distal C-terminus that mediates interaction with the scaffolding protein ankG (Figure 7; Chung, Jan, & Jan, 2006; Pan et al., 2006; Rasmussen et al., 2007). This interaction stabilizes Kv7 channels at the AIS (Benned-Jensen et al., 2016). While the ankG binding sequence is present in several of the neuronal Kv7 subfamily members, the binding motif of Kv7.3 appears to be the primary anchor at the AIS (Rasmussen et al., 2007). The reason for the differential importance of the ankG binding motifs remains elusive, but it could be explained by differential phosphorylation of the ankG binding motifs present in diverse Kv7 α subunits, as the binding to ankG can be regulated by phosphorylation (Xu & Cooper, 2015).

Kv7 function in Neurons

Kv7 channels underlie the neuronal “M current” observed in most brain neurons (Brown & Adams, 1980; Wang et al., 1998). The name stems from the fact that the M current is inhibited upon activation of muscarinic acetylcholine receptors, resulting in increased neuronal excitability. Due to their low-threshold activation, Kv7 channels can regulate the resting membrane potential and the action potential threshold at the AIS (reviewed in Brown & Passmore, 2009). However, as Kv7 channels display very slow activation kinetics, they do not contribute significantly to the action potential repolarization. Instead, they activate upon repetitive firing, on which they can exert a strong dampening effect. In agreement with their critical role in inhibiting repetitive firing, certain mutations in the genes encoding Kv7.2 and Kv7.3 cause benign familiar neonatal epilepsy (BFNE, formerly known as BFNC), a specific form of epilepsy that affects newborns (Biervert et al., 1998; Charlier et al., 1998; Singh et al., 1998). Kv7.4 mutations can cause DFNA2, a form of non-syndromic hearing loss, consistent with expression of this α subunit in the inner ear (Kubisch et al., 1999). Further, mutations in the non-neuronal member of this subfamily, Kv7.1, are among the primary causes of the inherited cardiac arrhythmia long QT syndrome, and the recessive Jervell and Lange-Nielsen syndrome, which in addition to cardiac arrhythmias features progressive hearing loss (Neyroud et al., 1997; Q. Wang et al., 1996).

The KvS (Kv5, Kv6, Kv8, and Kv9) Subfamily

Members of the Kv5, Kv6, Kv8, and Kv9 subfamilies of Kv channel α subunits are atypical in that they fail to produce currents in heterologous expression systems and are therefore referred to as the electrically silent Kv channels (KvS). Together these subfamilies comprise ten members, and all except Kv6.2 have a reported expression in brain (Table 1; reviewed in Bocksteins, 2016). The KvS α subunits have the same overall structure as the functional Kv α subunits and are equipped with a long N-terminus and a relatively short C-terminus (Figure 8). The lack of functional expression in these subfamilies appears, at least partly, to stem from the inability of KvS α subunits to assemble into homotetramers, with the unassembled channel α subunits being retained in the ER (Ottschytsch, Raes, Van Hoorick, & Snyders, 2002). While the KvS α subunits contain an N-terminal T1 tetramerization domain similar to Kv1–4 (Figure 8), these N-termini fail to interact with one another, which suggests that their homo-tetrameric assembly is not supported by their T1 domains (Post, Kirsch, & Brown, 1996). The KvS α subunits can, however, assemble with members of the Kv2 subfamily, an assembly that promotes KvS surface expression and results in functional Kv2/KvS heteromers in co-expressing heterologous cells (Ottschytsch et al., 2002). The biophysical profiles of Kv2/KvS heteromers differ from homo-tetrameric Kv2 channels, and KvS are therefore considered modulatory subunits of the Kv2 channels (Bocksteins & Snyders, 2012). In general, KvS co-expression reduces Kv2 current densities, except for Kv9.3, which enhances it. KvS α subunits can furthermore shift the voltage dependence of both activation and inactivation, as well as modify the kinetics of activation, inactivation, and/or deactivation of co-expressed Kv2 channels (Figure 8; reviewed in Bocksteins & Snyders, 2012). The degree to which Kv2/KvS complexes exist in vivo remains unclear, as most studies on these channels have been performed in heterologous expression systems. However, knockdown of certain KvS α subunits impacts neuronal excitability (e.g., Tsantoulas et al., 2012), supporting an in vivo role in ion channel function.

The KvS subfamily.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 8 A. Schematic overview of the domain structure of a KvS α subunit. B. Example of Kv2 modulation by a KvS subunit. Shown are Kv2.1 and hKv2.1/hKv8.2 currents recorded from HEK293 cells expressing Kv2.1 alone or in combination with Kv8.2. Currents were elicited by 200 ms voltage steps from −80 to +80 mV (10 mV increments) followed by a step to −40 mV. C. Bar diagram illustrating the reduction in current density observed upon co-expression of Kv2.1 and Kv8.2 compared to homomeric Kv2.1. Currents were recorded at +30 mV in HEK293 cells. D. Graph illustrating the prominent effect of Kv8.2 on the Kv2.1 voltage dependence of steady-state inactivation. Channels were inactivated for 20 s (Kv2.1, open circles) or 30 s (Kv2.1/Kv8.2, closed circles) at prepulse potentials ranging from −100 to +40 mV, followed by a test pulse to +60 mV to activate residual non-inactivated channels. The normalized amplitudes were plotted against the prepulse potentials and fitted with a Boltzmann function (n = 7–9). (B–D were adapted with permission from Smith et al., 2012.) E. Co-immunolabeling for the Kv8.2 and Kv2.1 α subunits in human retinal inner segments. Kv8.2 is present in both rod and cone inner segment membranes, where it is co-localized with Kv2.1. (Adapted from Gayet-Primo et al., 2018.)

KvS Accessory Proteins

Kv6.1 interacts with CaM in a calcium-dependent manner (O’Connell et al., 2010). The interaction is mediated through a C-terminal binding motif that is exclusively found in Kv6.1 and not in other KvS members (Figure 8). The possible binding of CaM to Kv2/Kv6.1 heteromers, and its potential impact, has not been determined.

KvS Subcellular Localization

The specific subcellular localization of KvS α subunits in neurons remains largely unknown. Kv8.2 α subunits have been localized in the inner segment of retinal photoreceptors, where they co-localize with Kv2 channels (Figure 8; Gayet-Primo, Yaeger, Khanjian, & Puthussery, 2018). However, in general, studies of the subcellular localization of the different KvS α subunits are lacking, including whether KvS subunits co-localize with Kv2 channels in the characteristic clusters observed in brain neurons. Such studies, as well as determining whether KvS α subunits can influence the subcellular localization of Kv2 channels in neurons, would add important knowledge to our current understanding of these intriguing electrically silent subunits.

KvS function in Neurons

Profiling of mRNA levels suggests that KvS α subunits are far more restricted in their cellular expression patterns than the broadly expressed Kv2 channels, making it possible that any in vivo role for KvS α subunits in modulating Kv2 currents would occur in a restricted, cell-specific manner. The neuronal functions of KvS α subunits are, however, quite unexplored, due to the lack of specific pharmacological agents that would distinguish KvS-containing channels, or antibodies to label endogenous KvS α subunits in tissue samples. As most studies on KvS channels have been performed in heterologous expression systems, whether regulation of Kv2 channels is the primary neuronal function of KvS subfamily members remains to be determined. Studies in retinal photoreceptor cells nevertheless support that Kv2.1 and Kv8.2 associate and co-localize in the inner segment of both rod and cone photoreceptors and together underlie the IKx current that stabilizes the dark resting potential and accelerates the voltage response to dim light (Beech & Barnes, 1989; Gayet-Primo et al., 2018). In support of this, certain mutations in the KCNV2 gene that encodes Kv8.2 cause the retinal disorder “cone-dystrophy with supernormal rod electroretinogram,” that leads to life-long visual loss (Wu et al., 2006).

The Kv10–12 Subfamilies

The members of the Kv10–Kv12 subfamilies are all orthologues of the Drosophila ether-à-go-go (EAG) channel and are often referred to as the “EAG superfamily.” They are also known as eag (Kv10), eag-related gene (erg) (Kv11), and eag-like (elk, Kv12) K+ channels. In total, the superfamily counts eight members that all exhibit neuronal expression at the mRNA level (Table 1). These α subunits contain very large N- and C-terminal cytoplasmic domains (Figure 9). The N-terminal is characterized by the presence of the EAG domain that consists of a cap sequence and a Per-Arnt-Sim (PAS) domain (Figure 9). The C-terminus contains a cyclic nucleotide-binding homology domain (CNBHD). However, this domain does not bind cyclic nucleotides, as the binding domain is occupied by the distal part of the CNBHD itself (reviewed in Bauer & Schwarz, 2018). Although all members of the Kv10–Kv12 subfamilies generate delayed rectifier-type channels when expressed in heterologous expression systems, the ionic currents generated by individual members of the three subfamilies have their own characteristic functional properties. Kv channels formed by Kv10 α subunits conduct delayed rectifier-type currents that activate with slow-activation kinetics (Figure 9). Characteristically, Kv10-mediated currents display activation kinetics that depend on the prepulse potential with accelerated activation kinetics at depolarized potentials (Ludwig et al., 1994). In contrast, Kv11-mediated currents display slow activation kinetics, but inactivate rapidly (Figure 9). As their recovery from inactivation is fast and their deactivation kinetics slow, Kv11 currents are largest upon repolarization (Figure 9). Kv12-mediated currents activate at more hyperpolarized potentials than do those mediated by Kv10 α subunits. They display some (Kv12.2) or no (Kv12.1, Kv12.3) inactivation. In contrast to Kv10 channels, their activation kinetics do not depend on the prepulse potential. The differences in gating characteristics between Kv channels formed by Kv10–Kv12 α subunits can at least partly be explained by sequence variations in the EAG domain that impacts channel gating (reviewed in Bauer & Schwarz, 2018). Kv channels from these three subfamilies are also distinctly regulated, with Kv10 channels regulated by intracellular calcium, Kv11 by extracellular K+, and Kv12 by external pH (reviewed in Bauer & Schwarz, 2018). Tetramerization of the component α subunits requires a coiled-coil domain in their distal C-terminus (the carboxyl assembly domain, CAD) and hetero-tetramerization is possible, but restricted to α subunits within their own subfamily (Figure 9; Jenke et al., 2003; Ludwig, Owen, & Pongs, 1997; Wimmers, Wulfsen, Bauer, & Schwarz, 2001). The subfamily-specific association is regulated by the C-terminal coiled-coil as well as unidentified regions in the N-terminus (Jenke et al., 2003; Lin et al., 2014).

The Kv10–Kv12 subfamilies.

The Voltage-Dependent K+ Channel FamilyClick to view larger

Figure 9 A. Schematic overview of the domain structure of a Kv10–Kv12 α subunit. The Kv10-associated regulatory CaM subunit is included. PAS: Per-Arnt-Sim; CNBHD: cyclic nucleotide-binding homology domain. B. Representative current trances obtained in Xenopus laevis oocytes expressing Kv10.2, Kv11.1, or Kv12.2 α subunits, as indicated. For Kv11.1 and Kv12.2, the applied voltage protocol is shown. For Kv10.2, currents were activated by voltage steps from −90 mV to +40 mV in 10 mV increments, and tail currents recorded at −80 mV. (Adapted with permission from Saganich et al., 1999; Trudeau, Titus, Branchaw, Ganetzky, & Robertson, 1999; Van Slyke et al., 2010.) C. Ribbon representation of the cryoEM structure of the rat Kv10.1 α subunit in complex with CaM. The transmembrane and extracellular domains are colored red, while the N- and C-termini are blue and yellow, respectively. CaM is shown in purple. The image was created with Swiss-PDB Viewer and PDB ID: 5K7L. D. Illustration of the structure in C as seen from the extracellular side to visualize how the same CaM molecule simultaneously binds the N- and C-terminal domains. Color coding is as in C.

Kv10–12 Accessory Proteins

Kv10.1 α subunits bind CaM in a calcium-dependent manner through three distinct binding motifs located in the N- and C-terminal domains (Figure 9; Schönherr, Löber, & Heinemann, 2000; Ziechner et al., 2006). CaM binding at calcium levels above 100 nM results in a potent inhibition of channels containing Kv10 α subunits (Schönherr et al., 2000). The crystal structure of the Kv10.1 α subunit in complex with CaM suggest that CaM binds the N- and C-termini to clamp the two domains, resulting in pore closing (Figure 9; Whicher & MacKinnon, 2016). The CaM binding domains are conserved in the related Kv10.2 α subunit but are absent in Kv11 and Kv12 subfamily members, making the CaM-dependent regulation unique to the Kv10 subfamily.

Kv10–12 Subcellular Localization

The subcellular localization of Kv10–Kv12 α subunits remains largely unknown. Experiments on Kv10.1 knockout mice demonstrate a presynaptic function of this subunit in granule cells of the cerebellum, where it was also detected by electron microscopy (Mortensen et al., 2015). Whether Kv10 α subunits also localize to other neuronal compartments has not been determined. The primary subcellular localization of Kv11 and Kv12 α subunits has not yet been defined.

Kv10–12 function in Neurons

The lack of specific pharmacological inhibitors for Kv10 and Kv12 channels has hampered the investigation of their native currents. Therefore, the current knowledge on these two subfamilies is based on studies in knockout animals. Most data suggest a presynaptic function of Kv10.1 α subunits, where they limit the action potential–induced calcium influx into the presynaptic terminals. Since channels formed from Kv10 α subunits display relatively slow activation kinetics, they do not impact presynaptic calcium levels significantly during single action potentials. However, as channel activation accelerates with depolarized potentials, Kv10.1-mediated currents activate faster during repeated action potentials, thereby impacting presynaptic calcium influx in a frequency- and pulse number-dependent manner (Mortensen et al., 2015). Specific blockers are available for Kv11-containing channels, and Kv11 currents can stabilize the resting membrane potential and cause frequency adaptation due to the progressive build-up of current during successive firings (reviewed in Bauer & Schwarz, 2018). However, studies on Kv11 currents are also sparse, since native Kv11 currents are reportedly relatively small and difficult to isolate. A role similar to Kv11 subfamily members’ has been reported for Kv12.2 α subunit, based on knockout studies (Zhang et al., 2010).

De novo mutations in KCNH1 that encode the Kv10.1 α subunit are linked to two neurological diseases, the Zimmermann-Laband and Temple-Baraitser syndromes (Kortüm et al., 2015; Simons et al., 2015). These syndromes have neurological features such as intellectual disability and epileptic seizures, but they are also characterized by extraneuronal characteristics, including facial dysmorphism and hypoplasia or aplasia of nails and terminal phalanges. Effects outside of the nervous system could be caused by the impact of Kv10.1-containing channels on cell cycle control and proliferation, and the α subunit is ectopically expressed in 70 percent of human cancers (Urrego, Tomczak, Zahed, Stühmer, & Pardo, 2014). Interestingly, all reported mutations cause gain-of-function effects in Kv10.1, perhaps consistent with the observation that Kv10.1 knockout mice develop normally (Ufartes et al., 2013). It suggests that, whereas absence of Kv10.1 expression can be tolerated, augmented activity of the channel is not. Mutations in the KCNH2 gene that encodes Kv11.1 are one of the common causes of the inherited cardiac arrhythmia long QT syndrome (Curran et al., 1995).

Conclusion

Much progress in understanding the structure, function, and regulation of Kv channels has been made since Kv currents were first described in the squid giant axon. Aided by the cloning of Kv channel α and auxiliary subunits, we have learned much about the biophysical and pharmacological properties of Kv channels formed by distinct subunit combinations. The development of reliable, subunit-specific antibodies has provided critical insights into their specific cellular and subcellular localization patterns, and the extent of their association with one another in native channel complexes. Classical biochemical experiments, and more recently, proteomics have begun to reveal the nature and identity of specific post-translational modifications and interacting partners. The integrated knowledge from these studies has allowed for a reliable correlation of specific Kv channel α and auxiliary subunit combinations with native neuronal currents. Molecular cloning studies revealed that the mammalian Kv channel family is not only large, but also very diverse. Although all Kv channels exhibit voltage activation and conduct K+ ions, they each have their individual biophysical and pharmacological characteristics, and display a variety of subcellular localization patterns, even within highly restricted sub-compartments. Their diversity in structure, function, expression, localization, and dynamic modulation provides neurons with a wide palette of Kv channels that can be utilized to fine-tune specific aspects of neuronal signaling. That the diversity is important is demonstrated by the large number of Kv channels associated with human disease, further underscoring that, while they exhibit many similarities, their functions are in many cases non-redundant.

Future Directions

We have learned a lot about the basic characteristics of different Kv channels since the first channel was cloned in 1987. However, not all Kv subfamilies are well described. The KvS and Kv10–Kv12 subfamilies still remain somewhat mysterious in regard to their neuronal functions. This is mainly due to the lack of the proper tools, such as specific pharmacological blockers and antibodies for these α subunits, such that they remain the “dark matter” of the ion channel universe. As many of these relatively unknown α subunits show strong neuronal expression and some are linked to neurological diseases, it will be important to develop those tools. Knockout studies of the different subunits should help clarify their neuronal functions.

Further, even with regard to the well-described Kv channel α and auxiliary subunits, we still have much to learn. It has become increasingly clear that Kv channel expression and function are not static features. Neuronal signaling pathways can dynamically impact Kv channel expression levels, localization, and function. For instance, many Kv channels display altered gene expression in response to prolonged changes in overall neuronal activity (Lee et al., 2015). There is a whole avenue of research ahead of us, with the aim to understand the regulation of Kv channel function and localization and its physiological impact. Further, we need to obtain the broader picture of how the regulation is mastered. This will require knowledge of the signaling networks that the individual Kv channels operate within. As indicated by the mosaic localization of Kv channels at the AIS (Figure 2), the local signaling networks at each of these sites will most likely differ. Proteomic characterization of different Kv channel complexes should help us delineate the associated signaling networks and their role in regulating function within the distinct subcellular compartments.

Finally, the studies on members of the Kv2 subfamily serve as a beautiful example that Kv channel function is not limited to functioning as a voltage-dependent pathway for the flux of K+ ions across the PM. In fact, the ability of Kv2 to remodel ER-PM junctions in a variety of cell types, including neurons, does not appear to require its K+ conductance (Kirmiz, Palacio, et al., 2018). This provides yet another prominent example of the non-conducting functions of Kv channels (Kaczmarek, 2006). The elucidation of the protein interaction partners of Kv channels should be instrumental in further defining the interplay between the diverse family of Kv channels and cellular function. Further, as also demonstrated in the Kv2 example, high-resolution imaging of the nanodomain subcellular structures associated with Kv channels could also provide important information in this context. Clarifying both the signaling networks of different Kv channels as well as the whole range of Kv functions, including those that do not involve K+ flux, should create a basis for us to understand why mutations in some Kv channel α subunits are disease-causing, and those of others are not.

Acknowledgements

Work in the Rasmussen laboratory is supported by the Novo Nordisk Foundation grant no. NNF17OC0028930 and Lundbeckfonden grant no. R273-2017-2988. Related work in the Trimmer lab is supported by National Institutes of Health grants R01 HL144071 and R21 NS101648.

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