Two-step voltage-sensor activation of the human KV7.4 channel and effect of a deafness-associated mutation.
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Nappi M, Frampton DJA, Kusay AS, Wang K, Yasarbas SS, Pozzi S, Miceli F, Liin SI, Taglialatela M, Pantazis A
Nat Commun 17 (1) - [2026-02-05; online 2026-02-05]
KCNQ4-encoded KV7.4 voltage-gated potassium channels are expressed in hair-cells of the inner ear. Loss-of-function variants in KCNQ4 cause non-syndromic progressive hearing loss (DFNA2). KV7.4 pore opening requires voltage-dependent conformational changes (activation) of the voltage-sensor domains (VSDs); however, how fast charge displacement during VSD activation is coupled to slow channel opening is currently unclear. Here, we optically tracked KV7.4 VSD activation with voltage-clamp fluorometry, leveraging two fluorophores and pulsed excitation, and found that VSD activation comprises several voltage-dependent transitions, some with kinetics and voltage-dependence matching those of channel opening and closing. The DFNA2-causing R216H mutation impairs VSD movement and channel opening by destabilizing the active VSD configuration, a result confirmed by molecular dynamics simulations. We propose that the KV7.4 VSD activates in two steps: a fast movement representing a first transition to an intermediate activation state, followed by slower component(s) that fully activate the VSD and drive channel opening.
Clinical Genomics Linköping [Service]
PubMed 41639121
DOI 10.1038/s41467-026-69249-8
Crossref 10.1038/s41467-026-69249-8
pmc: PMC12982505
pii: 10.1038/s41467-026-69249-8