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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Zhu, Wendy and Silva, Jonathan, "Dataset for Figure 1: Mechanisms of non-Covalent Subunit Regulation of Nav Channel Gating and Pharmacology" (2016). Digital Research Materials (Data & Supplemental files). 3.