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.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…This effect is strikingly similar to the action of the Kv7-channel-activator compound, retigabine, which induces a pronounced left shift of the activationvoltage relationship in M-currents recorded from sympathetic neurons. 29 Increased function of M-currents has been suggested to increase neuronal excitability, 7 which could be due to overactivation of hyperpolarizationactivated non-selective cation channels, resulting in secondary depolarizations. 30 The dramatic stabilization of activated states in comparison with closed states, induced by Kv7.5 p.Pro369Arg, is predicted to increase excitability and helps explain the severe phenotype of individual 4.…”

Optogenetic photochemical control of designer K+channels in mammalian neurons

“…Heteromultimeric channels composed of primarily Kv7.2 and Kv7.3 subunits underlie the M-current, a slow voltage-gated current in neurons and cardiac muscle that is activated at membrane potentials below action potential threshold (Brown and Passmore 2009). M-current is named as such because it is inhibited by muscarinic receptors, providing a potent mechanism for neurotransmitter modulation of excitability.…”

Morphological and functional diversity of first-order somatosensory neurons

“…KCNQ (K V 7.X) channels (reviewed by Brown and Passmore 2009), that are responsible for the slowly activating and noninactivating M currents, are present in DRG neurons. Retigabine, which activates K V 7, raises the action potential threshold and decreases the firing rate of sensory fibers (Rivera-Arconada and Lopez-Garcia 2006; Lang et al 2008).…”

“…Retigabine, which activates K V 7, raises the action potential threshold and decreases the firing rate of sensory fibers (Rivera-Arconada and Lopez-Garcia 2006; Lang et al 2008). The K V 7 blockers XE991 and linopirdine, in sympathetic neurons, switch phasic neurons to tonic (Brown and Passmore 2009).…”