Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine

Abstract

KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.

Subtype‐specific modulation of human KV7 channels by the anticonvulsant cannabidiol through a lipid‐exposed pore‐domain site

“…(a) Sequence alignment of the S4–S5 linker, S5 and S6 helices of hK V 7 subtypes reveals overlap between putative AO‐state coupling residues and the reported interaction sites of compounds known to modulate hK V 7 channel function. Coupling residues are indicated in bold, black text (Hou et al, 2020; Yang et al, 2022). Residues that cannabidiol (CBD) interacts with (based on coarse‐grained (CG) simulations) are highlighted in green.…”

“…What underlying mechanisms may explain the effects of CBD we observe in our study? Recently, Yang et al (2022) determined conserved residues along the S4–S5 linker, S5 and S6 helices of hK V 7.2 and hK V 7.3 channels that made important contributions to the electromechanical coupling of the voltage‐sensing domain to the pore domain. Mutation of these putative coupling residues led to dysfunctional channels, some of which could be partially rescued by retigabine.…”

Potassium channel‐related epilepsy: Pathogenesis and clinical features

“…63 Yang et al developed a Xenopus oocyte model based on three patients carrying variants in KCNQ2, which were LOF variants determined by cellular electrophysiologic studies, and these patients showed a 90% reduction in seizures upon administration of retigabine. 64 Recently, a novel AED, SF0034, was approved for use in the United States. Its therapeutic mechanism is similar to that of retigabine, and the efficacy of this drug is 5-fold higher than that of retigabine; however, its side effects limit the clinical application of this drug.…”

“… 74 EE and intellectual decline are GOF variants, and the use of retigabine eliminates the potassium channel electro‐mechanical (E‐M) caused by current disruption induced by KCNQ3 variant, thus leading to antiepileptic therapeutic effects. 64 However, the drug is still contraindicated in children due to its skin and retinal discoloration side effects.…”

“…Yang et al. developed a Xenopus oocyte model based on three patients carrying variants in KCNQ2 , which were LOF variants determined by cellular electrophysiologic studies, and these patients showed a 90% reduction in seizures upon administration of retigabine 64 . Recently, a novel AED, SF0034, was approved for use in the United States.…”