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<p><i>KCNQ4</i>-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 <i>KCNQ4</i> 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.</p>

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Two-step voltage-sensor activation of the human KV7.4 channel and effect of a deafness-associated mutation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Mario Nappi,
  • Damon J. A. Frampton,
  • Ali S. Kusay,
  • Kaiqian Wang,
  • S. Suheda Yasarbas,
  • Serena Pozzi,
  • Francesco Miceli,
  • Sara I. Liin,
  • Maurizio Taglialatela,
  • Antonios Pantazis

摘要

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.