Two-step voltage-sensor activation of the human K<sub>V</sub>7.4 channel and effect of a deafness-associated mutation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41639121.
- Also identified by DOI 10.1038/s41467-026-69249-8 and PMC identifier 12982505.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
KCNQ4-encoded K<sub>V</sub>7.4 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). K<sub>V</sub>7.4 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 K<sub>V</sub>7.4 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 K<sub>V</sub>7.4 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.
Medical subject headings
- KCNQ Potassium Channels
- Deafness