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 Ann Saito Loftus, 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 (Austin, Tex.)
Volume13
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

NAV1.5 Voltage-Gated Sodium Channel
Cardiac Myocytes
Smooth Muscle
Channelopathies
Pressure
Long QT Syndrome
Mutation
Irritable Bowel Syndrome
HEK293 Cells
Sudden Cardiac Death
Electric potential
Membrane Potentials
Smooth Muscle Myocytes
Muscle
Shear stress
Sodium Channels
Depolarization
Clamping devices
Chemical activation
Cells

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity. / Strege, Peter R.; Mercado-Perez, Arnaldo; Mazzone, Amelia; Saito Loftus, Yuri Ann; Bernard, Cheryl E.; Farrugia, Gianrico; Beyder, Arthur.

In: Channels (Austin, Tex.), Vol. 13, No. 1, 01.12.2019, p. 287-298.

Research output: Contribution to journalArticle

@article{c7ac5ab1f596482dba26a14a45c9163e,
title = "SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity",
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.",
keywords = "Electrophysiology, functional gastrointestinal disorder, ion channel, irritable bowel syndrome, mechanotransduction, voltage-gated sodium channel type 5",
author = "Strege, {Peter R.} and Arnaldo Mercado-Perez and Amelia Mazzone and {Saito Loftus}, {Yuri Ann} and Bernard, {Cheryl E.} and Gianrico Farrugia and Arthur Beyder",
year = "2019",
month = "12",
day = "1",
doi = "10.1080/19336950.2019.1632670",
language = "English (US)",
volume = "13",
pages = "287--298",
journal = "Channels",
issn = "1933-6950",
publisher = "Landes Bioscience",
number = "1",

}

TY - JOUR

T1 - SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity

AU - Strege, Peter R.

AU - Mercado-Perez, Arnaldo

AU - Mazzone, Amelia

AU - Saito Loftus, Yuri Ann

AU - Bernard, Cheryl E.

AU - Farrugia, Gianrico

AU - Beyder, Arthur

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

KW - Electrophysiology

KW - functional gastrointestinal disorder

KW - ion channel

KW - irritable bowel syndrome

KW - mechanotransduction

KW - voltage-gated sodium channel type 5

UR - http://www.scopus.com/inward/record.url?scp=85069263419&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069263419&partnerID=8YFLogxK

U2 - 10.1080/19336950.2019.1632670

DO - 10.1080/19336950.2019.1632670

M3 - Article

C2 - 31262209

AN - SCOPUS:85069263419

VL - 13

SP - 287

EP - 298

JO - Channels

JF - Channels

SN - 1933-6950

IS - 1

ER -