TY  - GEN
N2  - 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.
DO  - 10.7936/K7J102MF
DO  - DOI
AB  - 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.
AD  - Washington University in St. Louis
AD  - Washington University in St. Louis
T1  - Dataset for Figure 1: Mechanisms of non-Covalent  Subunit Regulation of Nav Channel Gating and Pharmacology
DA  - 2018-05-07
AU  - Zhu, Wendy
AU  - Silva, Jonathan R.
L1  - https://data.library.wustl.edu/record/3/files/ReadMe_sb_8e45577c_hXdxRy.txt
L1  - https://data.library.wustl.edu/record/3/files/Silva_Figure1.zip
LA  - eng
PY  - 2018-05-07
ID  - 3
L4  - https://data.library.wustl.edu/record/3/files/ReadMe_sb_8e45577c_hXdxRy.txt
L4  - https://data.library.wustl.edu/record/3/files/Silva_Figure1.zip
KW  - Medical engineering
KW  - biomedical engineering
TI  - Dataset for Figure 1: Mechanisms of non-Covalent  Subunit Regulation of Nav Channel Gating and Pharmacology
Y1  - 2018-05-07
L2  - https://data.library.wustl.edu/record/3/files/ReadMe_sb_8e45577c_hXdxRy.txt
L2  - https://data.library.wustl.edu/record/3/files/Silva_Figure1.zip
LK  - https://data.library.wustl.edu/record/3/files/ReadMe_sb_8e45577c_hXdxRy.txt
LK  - https://data.library.wustl.edu/record/3/files/Silva_Figure1.zip
UR  - https://data.library.wustl.edu/record/3/files/ReadMe_sb_8e45577c_hXdxRy.txt
UR  - https://data.library.wustl.edu/record/3/files/Silva_Figure1.zip
ER  -