Deletion of Trpm4 alters the function and expression of NaV1.5 channel in murine cardiac myocytes

Abstract

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca+ -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 block 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 immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs either in vivo or on 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 the myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+ current observed in the isolated cardiac myocytes. This reduction in Na+ current is explained by the observed decrease in protein expression of NaV1.5 in Trpm4-/- mice. This study suggests that Trpm4 expression impacts Na+ current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.