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Br J Pharmacol. 2009 Apr;156(8):1185-95. doi: 10.1111/j.1476-5381.2009.00111.x. Epub 2009 Mar 9.

Neural KCNQ (Kv7) channels.

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  • 1Department of Pharmacology, University College London, London, UK. d.a.brown@ucl.ac.uk

Abstract

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

PMID:
19298256
[PubMed - indexed for MEDLINE]
PMCID:
PMC2697739
Free PMC Article
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