KCNQ potassium channels: physiology, pathophysiology, and pharmacology

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Abstract

KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K+ channel α-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K+-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K+ current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K+ current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the IK,n in outer hair cells of the cochlea and IK,L in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K+ channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K+ channels.

Introduction

It is ironic that the reason some of the first K+ channel genes were discovered was because they produced phenotypic changes in Drosophila when spontaneously mutated. Examples such as Shaker and ether-a-go-go (eag) illustrate this point. This led to the discovery of mammalian and human homologues. However, it is only in the last few years that mutations in K+ channels have been linked with human disease, and the intriguing thing is that most of these mutant genes come from the same recently discovered family, KCNQ Rogawski, 2000, Jentsch, 2000. In the intervening years, other voltage-gated ion channels, such as Na+, Cl, and Ca2+, have taken centre stage, as they have been linked with human disease, and recent overviews of these channelopathies can be found in Cooper and Jan (1999), Lehmann-Horn and Jurkat-Rott (1999), Ashcroft (2000), and Lester and Karschin (2000).

Electrophysiologists have known for some time that voltage-gated K+ channels display considerable diversity. It is evident that in terms of voltage dependence, rates of activation and inactivation, as well as their pharmacology, almost every type of excitable cell has its own unique set or subset of K+ channels. Furthermore, the same type of cell, but with a different role, can have its K+ channels “tuned” by splice variants, almost literally in the case of auditory hair cells (e.g., Ramanathan et al., 1999). More recently, this heterogeneity of channels has been confirmed by molecular biologists: at least 8 families of K+ channel α-subunit genes have been cloned and identified, and each of these families contains a large number of individual members, numbering in total over 60 different subunits (Table 1).

Unlike voltage-gated Na+ or Ca2+ channels, the main K+ channel pore-forming protein is not translated from a single gene, but is made up of four separate subunits, which come together in the membrane to form the functional channel MacKinnon, 1991, Papazian, 1999. This has allowed considerable diversity of native K+ channels, as a wide range of heterotetramers is possible using different subunits from within the same subfamily. The K+ channel diversification is only increased by the co-assembly of nonpore-forming ß-subunits and the more recently realised possibility that subunits from very different families can come together to form functional physiologically relevant channels (e.g., Inagaki et al., 1995, Barhanin et al., 1996, Sanguinetti et al., 1996, Abbott et al., 1999).

This review concentrates on one K+ channel family, the KCNQ gene family, because although only recently identified, it has caused considerable excitement among the K+ channel fraternity as:

  • 1.

    most of the expressed family of channel genes may have a clear physiological correlate;

  • 2.

    this is one of the first K+ channel families where mutations have been directly linked to human diseases;

  • 3.

    there are at least some pharmacological agents that show selectivity for these currents, some of which may represent novel clinically useful drugs.

Section snippets

K+ channel families

In this review, I have conformed to the structural classification of Wei et al. (1996), and further developed by Grissmer (1997) and Pongs (1999), to group K+ channels firstly on their α-subunit (pore-forming) topology (i.e., number of transmembrane domains [TMDs] and pore loops [P-loops, P]). Secondly, the subfamilies are based on the homology of the amino acid sequence (Table 1 and Fig. 1). Where directly tested, the number of α-subunits that make a functional channel is four; however, for

KCNQ genes

KCNQ1, previously named KvLQT1, was first identified in a linkage study looking at some of the genetic causes of sudden death from cardiac arrhythmia (Wang, Q. et al., 1996). A number of chromosomal loci had been mapped to genetic loci, and one locus, responsible for over 50% of the inherited form of this disease (LQT1), was shown to code for a K+ channel, therefore termed KvLQT1. Detailed mapping of the gene encoding KCNQ1 has been performed Splawski et al., 1998, Neyroud et al., 1999. A

KCNQ currents

To date, KCNQ currents have been heterologously expressed in Xenopus oocytes Biervert et al., 1998, Schroeder et al., 1998, Yang et al., 1998, Wang et al., 1998, Schwake et al., 2000a. Chinese hamster ovary (CHO) cells Selyanko et al., 2000, Hadley et al., 2000, human embryonic kidney (HEK) 293 cells (Shapiro et al., 2000), and Sf9 cells (Barhanin et al., 1996). There are subtle differences in the results, possibly arising from the different expression systems, which will be discussed in

Channel blockers

A number of known K+-channel blocking drugs have been tested on the KCNQ family of channels (Table 5). Where tested, compounds such as 4-aminopyridine (4-AP), charybdotoxin, and 1-[2-(6-methyl-2-pyrydinil)ethyl]-4(4-methylsuphonylaminobenzoyl) piperidine (E-4031; an eag-related gene [erg] blocker) are ineffective on these currents. In general, Ba2+ ions produce at least a 50% inhibition at 1 mM. The channel-blocking activity of tetraethylammonium (TEA) has been more systematically studied

KCNQ physiological correlates

One major drawback in studying K+ channels has been the difficulty in matching up known functional currents with their corresponding K+-channel genes. As mentioned in Section 1, K+ channels, by their very structural nature, are more diverse than voltage-gated Na+ and Ca2+ channels. This has been elegantly reviewed with respect to shaker-like or Kv K+-channel families (Robertson, 1997). Unlike in other K+-channel gene families, four out of five of the KCNQ genes have now been tentatively

KCNQ modulation

All KCNQ channels are voltage-gated. Depolarisation of these channels increases the probability of their opening. However, other elements can modulate the channels' response to voltage change. KCNQ1 current has been shown to be enhanced when intracellular cAMP levels are raised with forskolin and 3-isobutyl-1-methylxanthine; this also occurs in KCNQ1+KCNE1 heteromultimers (Yang et al., 1997). This effect could be due to the PKA-mediated phosphorylation of the N-terminal consensus site (Table 3)

KCNQ pathophysiology

Wider ranging reviews on the links between ion channel mutations and human hereditary disease can be found in Cooper and Jan (1999), Lehmann-Horn and Jurkat-Rott (1999), and Ashcroft (2000). Here only human diseases related to members of the KCNQ family are considered.

Conclusions

As a family of K+ channels, KCNQ have far exceeded expectation in terms of the extent of their involvement in the physiology and pathophysiology of the body. KCNQ1 is an important K+ channel in the heart, inner ear, and the intestine. KCNQ2, KCNQ3, and possibly KCNQ5 are involved in the widely neuronally distributed M-current. KCNQ4 has an important role in the vestibular and auditory systems. KCNQ5 may have a role in skeletal muscle function, although this remains to be ascertained. Further

Acknowledgements

I would like to thank Susan Surguy for drawing Fig. 1 and proof reading the typescript. I am grateful to Drs. A. A. Selyanko and M. S. Shapiro, as well as Professors D. A. Brown and B. Hille, for allowing me to see their recent work before publication. I am also indebted to J. K. Hadley for allowing me to use data from her Ph.D. thesis.

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