title: Neural KCNQ (Kv7) channels.
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.
authors.affiliation: Department of Pharmacology, University College London, London, UK. d.a.brown@ucl.ac.uk
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Passmore
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials; D000320:Adrenergic Fibers / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D051656:KCNQ Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D051656:KCNQ Potassium Channels; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D011976:Receptors, Muscarinic; D000109:Acetylcholine; D011188:Potassium