Hot topic: Direct activation of neuronal KV7 channels by GABA and gabapentin – a novel mechanism for reducing neuronal excitability

The potassium channels KV7.2-KV7.5 (KCNQ2-5; GtoPdb target IDs 561-564) regulate neuronal excitability in the mammalian nervous system. The best characterised neuronal KV7 channels give rise to the M current (1) and are mediated predominantly by hetero-tetramers of KV7.2 and KV7.3 subunits (2). Established anticonvulsant agents such as retigabine are known to dampen neuronal excitability by activating neuronal KV7 channels. A tryptophan in the S5 transmembrane region of neuronal KV7 channels is essential for retigabine sensitivity with KV7.3 channels particularly sensitive. Importantly, this residue is not present in the cardiac KV7.1 (KCNQ1) channel, reducing the potential for cardiac side effects.

Now, a pair of studies (3, 4) has shown that this same region of the channel also contributes to a high affinity binding site for GABA and related metabolites (3). GABA activates channels comprised of KV7.3 and KV7.5, including heteromeric KV7.2/7.3 channels, with high potency but low efficacy. GABA does not, however, activate KV7.2 or KV7.4 homomeric channels or cardiac KV7.1 channels. The synthetic anticonvulsant and antinociceptive agent gabapentin activates the same KV7 subunits, although pregabalin does not, despite the overlapping therapeutic efficacy of these two compounds (4).

These results are of considerable pharmacological interest. They suggest a novel mechanism for GABA in regulating neuronal excitability through activation of KV7 channels. They indicate that both GABA and gabapentin will interfere with the action of therapeutically useful activators of KV7 channels such as retigabine. However, perhaps of most value given the relative difficulty in identifying potassium channel openers compared to blockers (5), this work identifies a new chemical class of potential therapeutic activators of neuronal KV7 channels that target an identified region of these channels.

Comments by Emma L. Veale (@Ve11Emma) and Alistair Mathie (@AlistairMathie)

(1) Brown, D.A. & Adams P.R. (1980). Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature, 283. 673-676. [PMID: 6965523].

(2) Wang H.S. et al. (1998). KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science, 282. 1890-1893. [PMID: 9836639].

(3) Manville R.W. et al. (2018). Direct neurotransmitter activation of voltage-gated potassium channels. Nature Commun., 9(1). 1847. [PMID: 29748663].

(4) Manville R.W. & Abbott G. (2018). Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels. Mol. Pharmacol., doi: 10.1124/mol.118.112953. [PMID: 30021858].

(5) Liin, S.I. et al. (2018). Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors. J. Gen. Physiol., doi: 10.1085/jgp.201711942. [PMID: 30002162].

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