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Kv5, Kv6, Kv8, and Kv9 Subunits: No Simple Silent Bystanders

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Kv5, Kv6, Kv8, and Kv9 Subunits: No Simple Silent Bystanders Published January 11, 2016 R e v i e w Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders Elke Bocksteins Laboratory for Molecular Biophysics, Physiology, and Pharmacology, Department for Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium Members of the electrically silent voltage-gated K+ (Kv) subfamilies (Kv5, Kv6, Kv8, and Kv9, collectively identified as electrically silent voltage-gated K+ channel [KvS] subunits) do not form functional homotetrameric channels but assemble with Kv2 subunits into heterotetrameric Kv2/KvS channels with unique biophysical properties. Unlike the ubiquitously expressed Kv2 subunits, KvS subunits show a more restricted expression. This raises the possibility that Kv2/KvS heterotetramers have tissue-specific functions, making them potential targets for the development of novel therapeutic strategies. Here, I provide an overview of the expression of KvS subunits in different tissues and discuss their proposed role in various physiological and pathophysiological processes. This overview demonstrates the importance of KvS subunits and Kv2/KvS heterotetramers in vivo and the importance of considering KvS sub- units and Kv2/KvS heterotetramers in the development of novel treatments. Kv2 channels Downloaded from The voltage-gated K+ (Kv) channel Kv2.1 plays a crucial functions in a host of different excitable and nonexcit- role in many cell types, with its contribution to various able cells depends on Kv2.1 channel diversity, which is processes depending on both its conductive and non- achieved through various mechanisms. These include conductive properties. For example, Kv2.1 channels con- posttranslational modifications of the Kv2.1 -subunits trol the action potential width in hippocampal neurons (e.g., phosphorylation and SUMOylation; Mohapatra during high-frequency stimulation (Du et al., 2000), and et al., 2007; Dai et al., 2009), association with auxiliary jgp.rupress.org they carry the augmented K+ current that triggers the -subunits (e.g., KChAP, AMIGO, and KCNE1-5 pro- apoptotic cascade in cortical neurons (Pal et al., 2003). teins; Kuryshev et al., 2000; McCrossan and Abbott, These two functions depend on Kv2.1-mediated K+ 2004; David et al., 2015), and heterotetramerization current. In contrast, Kv2.1 channels help control the with modulatory -subunits of the Kv5, Kv6, Kv8, and glucose-stimulated insulin secretion in human pancre- Kv9 subfamilies (Bocksteins and Snyders, 2012). Kv2.1 atic -cells by means of their interaction with the solu- channel diversity can be further increased through a on March 16, 2016 ble N-ethylmaleimide–sensitive factor (NSF) attachment combination of these different mechanisms. For exam- receptor protein syntaxin 1A (Dai et al., 2012). They ple, Kv2.1 subunits assemble with both the modulatory also induce the formation of junctions between the -subunit Kv6.4 and the auxiliary -subunit KCNE5 to ER and the plasma membrane in cultured hippocam- generate functional Kv2.1/Kv6.4/KCNE5 channels with pal neurons; an enhanced Kv2.1 expression increases biophysical properties distinct from those of Kv2.1, Kv2.1/ The Journal of General Physiology the amount of cortical ER that is in close proximity to KCNE5, or Kv2.1/Kv6.4 channels (David et al., 2015). the plasma membrane, and Kv2.1 cluster formation re- models the cortical ER from tubules into large, planar Kv5, Kv6, Kv8, and Kv9 subunits: The electrically silent structures (Fox et al., 2015). In both of these processes, Kv subunits the role of Kv2.1 channels is independent of their ability The members of the Kv5, Kv6, Kv8, and Kv9 subfami- to conduct ions. lies are electrically silent; they are collectively referred Kv2.1 channels are homotetramers of -subunits that to as the electrically silent Kv (KvS) channel subunits. are arranged around a central ion-conducting pore The first KvS subunits were cloned in 1992 by Drewe (Long et al., 2005). The ability to mediate their disparate et al. (1992), and in the following years additional KvS subunits were discovered and characterized. A more Correspondence to Elke Bocksteins: e l k e . b o c k s t e i n s @ u a n t w e r p e n . b e historical perspective on the discovery of KvS subunits, Abbreviations used in this paper: 4-AP, 4-aminopyridine; AVCN, ante- rior ventral cochlear nucleus; BAFME, benign adult familial myoclonic and the developments made in the subsequent years, is epilepsy; CDSR, cone dystrophy with supernormal rod electroretinogram; given in a previous review (Bocksteins and Snyders, DCN, dorsal cochlear nucleus; DRG, dorsal root ganglion; DSM, detrusor 2012). 10 KvS subunits have been identified to date: smooth muscle; FR, fast ripple; GABA, -aminobutyric acid; HIF, hypoxia- inducible factor; Kv, voltage-gated K+; KvS, electrically silent Kv; PASMC, pulmonary artery smooth muscle cell; PVCN, posterior ventral cochlear © 2016 Bocksteins This article is distributed under the terms of an Attribution–Noncom- nucleus; RMCA, rat middle cerebral artery; RT, reverse transcription; mercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative ScTx-1, stromatoxin 1; SNP, single nucleotide polymorphism; VSMC, vas- Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as de- cular smooth muscle cell. scribed at http://creativecommons.org/licenses/by-nc-sa/3.0/). The Rockefeller University Press J. Gen. Physiol. Vol. 147 No. 2 105–125 www.jgp.org/cgi/doi/10.1085/jgp.201511507 105 Published January 11, 2016 Downloaded from jgp.rupress.org on March 16, 2016 Figure 1. Subfamily-specific assembly into functional Kv channels. (A) Each subfamily is represented in a different color, with the lighter and darker shades representing a different subunit within the same subfamily. The Kv1–Kv4 subunits form functional homo- and heterotetrameric channels within their own subfamilies. Members of the electrically silent Kv subfamilies (Kv5, Kv6, Kv8, and Kv9) do not form functional homotetramers but heterotetramerize with Kv2 subunits to form functional channels. (B) Subfamily-specific Kv2/ KvS assembly is determined by interactions (represented in green) that involve both the N and C termini: an interaction between the 106 Kv5–Kv6 and Kv8–Kv9 channel subunits Published January 11, 2016 Kv5.1, Kv6.1–Kv6.4, Kv8.1, Kv8.2, and Kv9.1–Kv9.3. Al- compared with that of Kv2.1 homotetramers by affecting though each KvS subunit has unique characteristics, they the gating mechanism of Kv2.1/Kv6.4 heterotetramers. all have three features in common. These features are A comparison of gating current (IQ) recordings from discussed in more depth in a previous review (Bocksteins Kv2.1 homotetramers and Kv2.1/Kv6.4 heterotetra- and Snyders, 2012) and will therefore only be shortly mers reveals a hyperpolarized second component in the discussed here. First, unlike the Kv1–Kv4 subunits, KvS charge (Q) versus voltage (V) distribution curve of the subunits do not form functional homotetrameric chan- heterotetramers (Fig. 1 D). The voltage dependence of nels when expressed alone in heterologous expression this hyperpolarized charge movement corresponds with systems (Fig. 1 A). Based on sequence homology, KvS the Kv6.4-induced hyperpolarizing shift in voltage- subunits appear to possess several hallmarks of a typi- dependent inactivation (Bocksteins et al., 2012). cal Kv -subunit: six transmembrane segments (S1–S6) with several positive residues on S4 that may function as Physiological role of Kv2/KvS heterotetramers the main voltage-sensing component, the K+ signature in different tissues sequence GYG on the pore loop between S5 and S6, and Unlike the ubiquitously expressed Kv2.1, KvS subunits cytoplasmic N and C termini (Bocksteins and Snyders, show a more restricted expression, suggesting that Kv2/ 2012). However, when expressed alone, KvS subunits KvS heterotetramers have tissue-specific functions. This is do not generate functional channels at the plasma supported by the increasing number of publications in membrane because of their retention in the endoplas- which the contribution of KvS subunits to different physi- Downloaded from mic reticulum. Second, KvS subunits heterotetramerize ological and pathophysiological processes in various cells with Kv2 subunits but not with members of the Kv1, Kv3, has been demonstrated. KvS expression in different tis sues and Kv4 subfamilies to generate functional channels at and cell types is presented in Table 1 and Fig. 2, and the the plasma membrane (Fig. 1 A). This subfamily-specific proposed role of KvS subunits in these cells is summa- assembly depends, at least for Kv2.1 and Kv6.4 subunits, rized in Table 2 and discussed in the following paragraphs. on both an interaction between the Kv2.1 and Kv6.4 N terminus and an interaction between the N terminus of Neural tissues jgp.rupress.org Kv2.1 and the C terminus of Kv6.4 (Fig. 1 B; Bocksteins Central nervous system. Numerous neurons in the cen- et al., 2014). In contrast, the N-terminal tetramerization tral nervous system express Kv2.1, and several studies domain T1 is assumed to be the only determinant of the have suggested a role for KvS subunits in these Kv2-ex- subfamily-specific assembly of the Kv1–Kv4 subunits: tet- pressing neurons. For example, Kv2.1 contributes to ramerization between members of the same subfamily is the slowly inactivating K+ current in rat neocortical py- promoted by a compatible T1 domain, whereas hetero- ramidal neurons (Guan et al., 2007) to regulate the fir- on March 16, 2016 tetramerization between subunits of different subfamilies ing rate (Guan et al., 2013). This Kv2-mediated current is prevented by an incompatible T1 domain (Li et al., shows a voltage dependence of activation and inactivation 1992; Shen et al., 1993; Lee et al., 1994; Shen and that is shifted in the hyperpolarized direction compared Pfaffinger, 1995; Xu et al., 1995). Third, KvS subunits with that of heterologously expressed Kv2 channels.
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