Neural KCNQ (Kv7) channels

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.