Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel

Arthur Beyder, James L. Rae, Cheryl Bernard, Peter R. Strege, Frederick Sachs, Gianrico Farrugia

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

The voltage-sensitive sodium channel Nav1.5 (encoded by SCN5A) is expressed in electromechanical organs and is mechanosensitive. This study aimed to determine the mechanosensitive transitions of Nav1.5 at the molecular level. Nav1.5 was expressed in HEK 293 cells and mechanosensitivity was studied in cell-attached patches. Patch pressure up to -50 mmHg produced increases in current and large hyperpolarizing shifts of voltage dependence with graded shifts of half-activation and half-inactivation voltages (δV1/2) by -0.7 mV mmHg-1. Voltage dependence shifts affected channel kinetics by a single constant. This suggested that stretch accelerated only one of the activation transitions. Stretch accelerated voltage sensor movement, but not rate constants for gate opening and fast inactivation. Stretch also appeared to stabilize the inactivated states, since recovery from inactivation was slowed with stretch. Unitary conductance and maximum open probability were unaffected by stretch, but peak current was increased due to an increased number of active channels. Stretch effects were partially reversible, but recovery following a single stretch cycle required minutes. These data suggest that mechanical activation of Nav1.5 results in dose-dependent voltage dependence shifts of activation and inactivation due to mechanical modulation of the voltage sensors.The heart, gastrointestinal tract and skeletal muscle are examples of electromechanical systems - excitable tissues with mechanical function. In such systems, mechano-electrical feedback is a process by which mechanical stimuli affect electrical performance. Electrical excitability of electromechanical systems is mediated by voltage-gated ion channels. These are proteins that are embedded in cell membranes and conduct ions in response to voltage shifts. In this study, we examined the effects of mechanical stretch on performance of a voltage gated sodium selective ion channel (Nav1.5) found in the heart and gut. Stretch had effects on various functional aspects of these channels. We showed that stretch increased peak sodium current, shifted the voltage dependence of activation and channel availability, and stabilized inactivation. These findings suggest the involvement of Nav1.5 in mechano-electrical feedback.

Original languageEnglish (US)
Pages (from-to)4969-4985
Number of pages17
JournalJournal of Physiology
Volume588
Issue number24
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Physiology

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