Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes.

Lijo Cherian Ozhathil,Jean-Sébastien Rougier,Daniela Ross-Kaschitza,Maria C Essers,Hugues Abriel,Prakash Arullampalam

doi:10.3390/ijms22073401

Abstract

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca2+-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in myocytes. Hearts from Trpm4−/− mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na+ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na+ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Nav1.5 function in murine cardiac myocytes.

Highlights

Introduction published maps and institutional affilThe cardiac Ca2+ -activated non-selective cation (NSca) currents were first measured in cultured rat neonatal myocytes in the early 1980s [1]
To investigate the role of Transient receptor potential melastatin member 4 (TRPM4) on mouse cardiac electrical activity, first we evaluated the expression of TRPM4 in different compartments of the heart: the atria, ventricles, and isolated ventricular myocytes
Since a strong expression of TRPM4 has been previously reported in the colon, we used it as a positive control in wild type (WT)

Summary

Introduction

Introduction published maps and institutional affilThe cardiac Ca2+ -activated non-selective cation (NSca) currents were first measured in cultured rat neonatal myocytes in the early 1980s [1]. The molecular identities of these current components remained largely unknown until a member of TRPM family, TRPM4b, was cloned [2,3,4,5], which was found to share the biophysical properties of a native NSca current from human atrial myocytes [6]. Instead, both are activated by an increase in intracellular Ca2+ , and voltage further modulates its gating, resulting in an outwardly rectifying current [7,8,9]. Both are activated by an increase in intracellular Ca2+ , and voltage further modulates its gating, resulting in an outwardly rectifying current [7,8,9]

Methods

Results

Conclusion