title: Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations.
abstract: KCNQ1 is a voltage-gated potassium channel that is modulated by the beta-subunit KCNE1 to generate IKs, 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 IKsdeactivation. 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 IKsdeactivation and provide a key step toward developing mechanism-based therapies.
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Peng
authors.affiliation: Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Barro-Soria
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Sampson
authors.affiliation: Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Larsson
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D005260:Female; D005470:Fluorometry / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D007700:Kinetics; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D014982:Xenopus laevis
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated