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Loss-of-function variants in\n                    <jats:italic>KCNQ4<\/jats:italic>\n                    cause non-syndromic progressive hearing loss (DFNA2). K\n                    <jats:sub>V<\/jats:sub>\n                    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\n                    <jats:sub>V<\/jats:sub>\n                    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\n                    <jats:sub>V<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-69249-8","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T02:36:44Z","timestamp":1770259004000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Two-step voltage-sensor activation of the human KV7.4 channel and effect of a deafness-associated mutation"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1243-0935","authenticated-orcid":false,"given":"Mario","family":"Nappi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon J. 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