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• W2751160432 abstract "Background: Co-assembly of cardiac Na + channels (Na v 1.5) with β subunits modifies channel gating, expression, and post-translational modification. β subunit mutations have been linked to the Brugada and Long QT Syndromes, and atrial fibrillation (AF). Hypothesis: We tested whether β 3 subunits regulate Nav.1.5 ionic current and drug response by modulating the voltage sensing domains (VSDs). Methods: The Na V 1.5 α subunit contains four domains (DI-DIV), each with its own voltage sensing domain (VSD). We previously created four DNA constructs that carried a cysteine within a single VSD. Channels expressed in Xenopus oocytes and these cysteines were labeled with TAMRA-MTS fluorophores. Ionic current and fluorescence emission that tracked VSD conformation were simultaneously recorded using the cut-open configuration with and without β 3 . Results: Steady state inactivation is significantly right shifted by β 3 (V 1/2 = -88.9 ± 1.1 SEM (with, +β 3 ) and -97.8 ± 1.5 (without, -β 3 ), p=0.002, n=4). β 3 also right shifts DIII-VSD activation (V 1/2 = -93.0±2.3 +β 3 , V 1/2 = --114.8±0.8 -β 3 , p=0.001, n=4), while modestly left-shifting channel activation, suggesting enhanced DIII-VSD to pore coupling (V 1/2GV -V 1/2FV =55.0 ± 4.0 +β 3 , V 1/2GV -V 1/2FV =73.6 ± 2.4 -β 3 , n=4). DI and DII were not affected, while DIV was modestly shifted, consistent with DIII/DIV cooperativity. Extracellular domain AF-linked β 3 mutations, R6K and L10P, further enhance DIII-VSD to pore coupling (V 1/2GV -V 1/2FV =34.1 ± 5.8, (R6K), V 1/2GV -V 1/2FV =41.5 ± 4.7 (L10P), n=4). β 3 nearly abolishes stabilization of the DIII-VSD by lidocaine (DIII FV shift by lidocaine: ΔV 1/2 lido=-27.71 ± 12.23 (+β 3 ), ΔV 1/2 lido=-65.44 ± 3.83 (-β 3 ), n=3). The conservative R6K mutation exacerbates this effect, suggesting a cation-pi interaction with Na V 1.5. W1684 is co-localized with the DIII-VSD, and W1684A disrupted β 3 modification of channel gating and the DIII lidocaine interaction. Conclusions: β 3 modifies Nav1.5 gating by increasing DIII-VSD coupling to the pore via interaction with W1684. AF β 3 mutants further enhance DIII-VSD to pore coupling. The differential lidocaine response caused by WT and AF β 3 mutants suggests a molecular mechanism whereby the lidocaine response is patient and heart-chamber specific." @default.
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• W2751160432 date "2015-11-10" @default.
• W2751160432 modified "2023-09-24" @default.
• W2751160432 title "Abstract 17379: Atrial Fibrillation Mutations in β3 Subunits Enhance DIII Voltage Sensing Domain Coupling to Channel Activation Which Inhibits Lidocaine Blockade" @default.
• W2751160432 doi "https://doi.org/10.1161/circ.132.suppl_3.17379" @default.
• W2751160432 hasPublicationYear "2015" @default.
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