SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity

Peter R. Strege, Arnaldo Mercado-Perez, Amelia Mazzone, Yuri A. Saito, Cheryl E. Bernard, Gianrico Farrugia, Arthur Beyder

Research output: Contribution to journalArticle

Abstract

SCN5A is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel NaV1.5. The influx of Na+ through NaV1.5 produces a fast depolarization in membrane potential, indispensable for electrical excitability in cardiomyocytes and important for electrical slow waves in GI smooth muscle. As such, abnormal NaV1.5 voltage gating or mechanosensitivity may result in channelopathies. SCN5A mutation G615E–found separately in cases of acquired long-QT syndrome, sudden cardiac death, and irritable bowel syndrome–has a relatively minor effect on NaV1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-NaV1.5 in HEK-293 cells was examined by shear stress on voltage- or current-clamped whole cells or pressure on macroscopic patches. Unlike WT, voltage-clamped G615E-NaV1.5 showed a loss in shear- and pressure-sensitivity of peak current yet a normal leftward shift in the voltage-dependence of activation. In current-clamp, shear stress led to a significant increase in firing spike frequency with a decrease in firing threshold for WT but not G615E-NaV1.5. Our results show that the G615E mutation leads to functionally abnormal NaV1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalChannels
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2019

Keywords

  • Electrophysiology
  • functional gastrointestinal disorder
  • ion channel
  • irritable bowel syndrome
  • mechanotransduction
  • voltage-gated sodium channel type 5

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

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