Molecular Determinants of KCNQ (K_v7) K⁺Channel Sensitivity to the Anticonvulsant Retigabine

Abstract

Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K ϩ channels are critical for establishing and stabilizing the resting potential of neurons, a loss of K ϩ channels could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, an autosomal dominant epilepsy of infancy, is caused by mutations in KCNQ2 or KCNQ3 K ϩ channel genes. Because these channels contribute to the native muscarinic-sensitive K ϩ current (M current) that regulates excitability of numerous types of neurons, KCNQ (K v 7) channel activators would be effective in epilepsy treatment. A compound exhibiting anticonvulsant activity in animal seizure models is retigabine. It specifically acts on the neuronally expressed KCNQ2-KCNQ5 (K v 7.2-K v 7.5) channels, whereas KCNQ1 (K v 7.1) is not affected. Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug. We identified a single tryptophan residue within the S5 segment of KCNQ3 and also KCNQ2, KCNQ4, and KCNQ5 as crucial for the effect of retigabine. Furthermore, heteromeric KCNQ channels comprising KCNQ2 and KCNQ1 transmembrane domains (attributable to transfer of assembly properties from KCNQ3 to KCNQ1) are retigabine insensitive. Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity.

Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

“…Retigabine, which activates KCNQ2, KCNQ3, KCNQ4, and KCNQ5, but not KCNQ1, channels (25), augmented the M-type current, as did ZnPy, a potent opener of all KCNQ channels except KCNQ3 (39). In addition to increasing M-type current amplitude at saturating voltages, both openers also produced hyperpolarizing shifts in V 1/2 and caused marked slowing of deactivation kinetics, effects that have been reported for KCNQ channels.…”

“…Retigabine, an antiepileptic drug that was recently approved for clinical use, has been shown to activate native M-type currents (34), as well as KCNQ2, KCNQ3, KCNQ4, and KCNQ5 currents (25). A tryptophan residue in the S5 segment of KCNQ subunits is crucial for the effects of retigabine (25), although additional residues have also been implicated (16).…”

PD-118057 contacts the pore helix of hERG1 channels to attenuate inactivation and enhance K + conductance

“…Two key residues for retigabine binding to KCNQ3 channels (L314 and L338) (18) align with two Leu residues (L622 and L646) in hERG1. The agonist activity of retigabine is mainly attributed to a shift in the voltage dependence of activation to more hyperpolarized potentials, but an accelerated activation and slowed deactivation (19,20), and increased P o of single channels (21) also contributes to its agonist action.…”

Molecular Targets for Antiepileptic Drug Development

“…It was proposed that retigabine binds to a hydrophobic pocket formed when the channel opens and that this explains the strong shift in the voltage-dependence of activation. 152,153 Several other classes of compounds have been shown to act as KCNQ2-5 channel openers, including benzamides, benzisoxazoles, and phenylacrylamides. 25,138 Some of these protect against seizures in animal models and are more specific for KCNQ channels than is retigabine, confirming that opening of KCNQ channels per se is an anticonvulsant mechanism.…”