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Grant/Award Number and Agency

American Heart Association 15PRE25080073 (Wandi Zhu); Burroughs Wellcome Fund Career Award at the Scientific Interface 1010299 (Jonathan R. Silva)


Voltage-gated Na+ (NaV) channels comprise a macromolecular complex, whose members tailor their function according to cell type. Key members are the non-covalently bound NaV ?1 and ?3 subunits that regulate channel gating, expression, and pharmacology. To probe the molecular basis of this regulation, we applied voltage-clamp fluorometry to measure how the ?-subunits affect conformations within the cardiac NaV channel (NaV1.5) voltage-sensing domains (VSDs). The pore-forming NaV1.5 ?-subunit contains four domains (DI-DIV), each with a VSD. Our results show that ?1 and ?3 regulate NaV1.5 by altering DIII- and DIV-VSD activation, an interaction that is significantly altered by atrial fibrillation-variants in both ? subunits. ?1 and ?3 strongly affected the interaction of Class Ib anti-arrhythmic drugs, lidocaine and ranolazine, with the DIII-VSD. Our results demonstrate that ?1 and ?3 regulation of the NaV1.5 VSDs can significantly determine NaV1.5 pathology and its therapeutic response.

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This work is licensed under a Creative Commons Attribution 4.0 License.

Academic Affiliation

Washington University in St. Louis