Document Type

Data

Embargo Period

11-21-2017

Grant/Award Number and Agency

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

Description

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.

Start Date

2016

End Date

2016

Creative Commons License

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

Academic Affiliation

Washington University in St. Louis

Available for download on Tuesday, November 21, 2017

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