The K_V7 (KCNQ)

The K_V7 family of K⁺ channels is part of the larger voltage-dependent K⁺ channels superfamily. In a family that comprises five members, four of them have been linked to channelopathies highlighting the functional importance of these channels.

Family of voltage-gated K⁺ channels

K⁺ channels are probably the most diverse class of ion channels with over 70 human genes described to date. Within the K⁺ channels the voltage-sensitive class is the most heterogeneous with at least 6 identified subfamilies of genes. The voltage-gated K⁺ channels have several key functions in both excitable and non-excitable cells and indeed, several genetic diseases have been ascribed to mutations in these channels. Surprisingly, many of the mutations in K_V channels causing disease seem to converge in one particular family: The K_V7 subfamily in which, four out of five members have been linked to channelopathies (genetic diseases caused by ion channel malfunction) (see Table 1).

The K_V7 subfamily shares the overall topology of the voltage-gated K⁺ superfamily: six transmembrane domains, a single pore loop (P-loop) and intracellular N- and C-termini.

The fourth transmembrane domain (S4) that probably acts as the voltage sensor shows the expected six positively charged amino acids, except in K_V7.1 where there are only four. As in the voltage-gated superfamily, the functional channel is a tetramer. Save for K_V7.1 that has only been shown to exist as a homomer, all the other members of the family can function as heteromer^1,2. Below is a brief summary of the current knowledge on the members of the K_V7 subfamily.

K_V7.1 (KCNQ1) and cardiac arrhythmias

K_V7.1 (also known as K_vLQT1) was the first member of the family to be recognized. The channel was identified in a linkage study looking for the genetic basis of sudden death from cardiac arrhythmia³. It was found that K_V7.1 together with the β subunit KCNE1 (Isk) underlay the cardiac IKs current that is responsible for controlling the duration of the action potential in the human heart^4,5. Indeed, mutations in either subunit are responsible for about half of the hereditary cases of long QT syndrome (a form of cardiac arrhythmia). A more severe hereditary disease is Jervell and Lange-Nielsen syndrome (JLNS), where mutations in K_V7.1 cause congenital deafness in addition to cardiac arrhythmia, indicating that the channel is also involved in K⁺ recycling in the inner ear. K_V7.1 is also expressed in epithelial cells of several tissues including intestine, lung and stomach.

In epithelial tissue, K_V7.1 appears to interact mainly with another β subunit called KCNE3 (MIRP2) that confers different properties to the channel and has been implicated in physiological functions such as: regulation of acid secretion in the stomach and Cl^– secretion into the colon^6,7.

Finally, a recent report has described the direct interaction between K_V7.1 and K_V11.1 (HERG) another prominent cardiac K⁺ channel that is the molecular correlate of the I_Kr current. This interaction resulted in altered localization and biophysical properties of K_V11.1 currents, indicating that K_V7.1 expression may functionally modulate I_Kr currents¹⁴.

K_V7.2 (KCNQ2) and K_V7.3 (KCNQ3): M-current and epilepsy

K_V7.2 and K_V7.3 were identified on the basis of their homology to K_V7.1 and also by positional cloning in families with a neonatal form of epilepsy, benign familial neonatal convulsions (BNFC)⁸. Mutations in either subunit can cause the disease and both subunits are expressed mainly in neuronal tissue with expression patterns that are largely overlapping, indicating that they may form a single tetrameric channel in vivo. Indeed, heteromers of K_V7.2 and K_V7.3 were found to be the molecular correlate of the so called M-current⁹.

This current, that was described more than twenty years ago, is a slowly activating and deactivating K⁺ current that can be inhibited by activation of a number of G-protein coupled receptors including muscarinic acethylcholine receptors and hence its name. M-channels open and close at rates that are about 100 times slower than those of the channels that underlay fast action potentials, therefore M-channels allow single action potentials but oppose repetitive firing.

From this, it is easy to understand how mutations in the components of the M-channel that result in current reduction can induce neuronal hyperexcitability and thus epilepsy. Interestingly, the ability of the M-channel to control neuronal hyperexcitability and the fact that its components K_V7.2 and K_V7.3 are expressed in sensory neurons from dorsal root ganglia has suggested that this channel may be an attractive therapeutic target for the control of pain¹⁰.

K_V7.4 (KCNQ4) and hearing loss

In contrast with the other members of the K_V7 subfamily, the expression pattern of K_V7.4 is highly restricted. The channel is almost exclusively expressed in the inner ear and in tracks of the central auditory pathways¹. Consistent with a key role in auditory function, mutations in K_V7.4 cause a dominant slowly progressing form of hearing loss termed DFNA.2¹¹, K_V7.4 can also form heteromers with K_V7.3 although the physiological significance of the heteromeric channel is not clear.

K_V7.5 (KCNQ5) and M-current diversity

K_V7.5 was the latest member of the family to be cloned and it remains the less studied. It is the only member of the subfamily that is yet to be linked to a hereditary disease. It is widely expressed in the brain and it has been shown to form heteromers with K_V7.3 that behave like M-type channels, thus raising the possibility that it contributes to M-current diversity^12,13.

References

1. Jentsch, T.J. (2000) Nat. Rev. 1, 21.
2. Robbins, J. (2001) Pharmacol. Ther. 90, 1.
3. Wang, Q. et al. (1996) Nat. Genet. 12, 17.
4. Barhanin, J. et al. (1996) Nature 384, 78.
5. Sanguinetti, M.C. et al. (1996) Nature 384, 80.
6. Schroeder, B.C. et al. (2000) Nature 403, 196.
7. Grahammer, F. et al. (2001) Gastroenterology 120, 1363.
8. Biervert, C. et al. (1998) Science 279, 403.
9. Wang, H.S. et al. (1998) Science 282, 1890.
10. Passmore, G.M. et al. (2003) J. Neurosci. 23, 7227.
11. Kubisch, C. et al. (1999) Cell 96, 437.
12. Schroeder, B.C. et al. (2000) J. Biol. Chem. 275, 24089.
13. Lerche, C. et al. (2000) J. Biol. Chem. 275, 223.
14. Ehrlich, J. R. et al. (2004) J. Biol. Chem. 279, 1233.