SCN5A variant R222Q generated abnormal changes in cardiac sodium current and action potentials in murine myocytes and Purkinje cells.

Daniel LL, Yang T, Kroncke B, Hall L, Stroud D, Roden DM
Heart Rhythm. 2019 16 (11): 1676-1685

PMID: 31125670 · PMCID: PMC6825529 · DOI:10.1016/j.hrthm.2019.05.017

BACKGROUND - The cardiac sodium channel (SCN5A) mutation R222Q neutralizes a positive charge in the domain I voltage sensor. Mutation carriers display very frequent ectopy and dilated cardiomyopathy.

OBJECTIVES - To describe the effect of SCN5A R222Q on murine myocyte and Purkinje fiber electrophysiology, and identify underlying mechanisms.

METHODS - We generated mice carrying humanized wild-type (H) and mutant (RQ) SCN5A channels. We characterized whole-heart and isolated ventricular and Purkinje myocyte properties.

RESULTS - RQ/RQ mice were not viable. I from RQ/H ventricular myocytes displayed increased "window current" and hyperpolarizing shifts in both inactivation and activation compared to H/H, as previously reported in heterologous expression systems. Surprisingly, action potentials were markedly abbreviated in RQ/H myocytes (action potential durations at 90% repolarization: 12.6 ± 1.3 ms vs 29.1 ± 1.0 ms in H/H, P < .01, n = 10 each). We identified a large [K]-dependent outward gating pore current in RQ/H but not H/H myocytes, and decreasing [K] elicited early afterdepolarizations (EADs) and triggered activity in isolated myocytes and ectopic beats in whole hearts. Further, RQ/H Purkinje cells displayed striking, consistent low-voltage EADs. In vivo, however, RQ/H mice displayed little ectopy and contractile function was normal.

CONCLUSION - While SCN5A R222Q increases plateau inward sodium current, action potentials were unexpectedly shortened, likely reflecting an outward gating-pore current. Low extracellular potassium increased this pore current, and was arrhythmogenic in vitro and ex vivo.

Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

MeSH Terms (12)

Action Potentials Alleles Animals Disease Models, Animal Echocardiography Electrocardiography Mice Mice, Transgenic Myocytes, Cardiac NAV1.5 Voltage-Gated Sodium Channel Purkinje Cells Sodium Channels

Connections (3)

This publication is referenced by other Labnodes entities: