A common SCN5A variant alters the responsiveness of human sodium channels to class I antiarrhythmic agents

Mossaab Shuraih, Tomohiko Ai, Matteo Vatta, Yoshiro Sohma, Eileen M. Merkle, Erica Taylor, Zhaohui Li, Yutao Xi, Mehdi Razavi, Jeffrey A. Towbin, Jie Cheng

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13 Citations (Scopus)

Abstract

Pharmacological Modification by SCN5A Polymorphism. Background: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. Methods and Results: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) define the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 μM) caused similar extent of tonic block reduction of sodium currents at -120 mV in WT and S524Y. Surprisingly, quinidine (20 μM) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22°C (Ki: WT, 51.3 μM; S524Y, 20.3 μM). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (τ = 88.6 ± 7.9 s vs 41.9 ± 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37°C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 μM), but not by mexiletine (100 μM). Conclusion: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response.

Original languageEnglish
Pages (from-to)434-440
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume18
Issue number4
DOIs
Publication statusPublished - 2007 Apr 1

Keywords

  • Patch-clamp
  • Pharmacology
  • Polymorphism
  • SCN5A
  • Sodium channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Shuraih, M., Ai, T., Vatta, M., Sohma, Y., Merkle, E. M., Taylor, E., Li, Z., Xi, Y., Razavi, M., Towbin, J. A., & Cheng, J. (2007). A common SCN5A variant alters the responsiveness of human sodium channels to class I antiarrhythmic agents. Journal of Cardiovascular Electrophysiology, 18(4), 434-440. https://doi.org/10.1111/j.1540-8167.2007.00777.x