Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations

Gary Peng, Rene Barro-Soria, Kevin J. Sampson, H. Peter Larsson, Robert S. Kass

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


KCNQ1 is a voltage-gated potassium channel that is modulated by the beta-subunit KCNE1 to generate I Ks, the slow delayed rectifier current, which plays a critical role in repolarizing the cardiac action potential. Two KCNQ1 gain-of-function mutations that cause a genetic form of atrial fibrillation, S140G and V141M, drastically slow I Ks deactivation. However, the underlying gating alterations remain unknown. Voltage clamp fluorometry (VCF) allows simultaneous measurement of voltage sensor movement and current through the channel pore. Here, we use VCF and kinetic modeling to determine the effects of mutations on channel voltage-dependent gating. We show that in the absence of KCNE1, S140G, but not V141M, directly slows voltage sensor movement, which indirectly slows current deactivation. In the presence of KCNE1, both S140G and V141M slow pore closing and alter voltage sensor-pore coupling, thereby slowing current deactivation. Our results suggest that KCNE1 can mediate changes in pore movement and voltage sensor-pore coupling to slow I Ks deactivation and provide a key step toward developing mechanism-based therapies.

Original languageEnglish (US)
Article number45911
JournalScientific reports
StatePublished - Apr 6 2017

ASJC Scopus subject areas

  • General


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