Background Transient Receptor Potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, 3 and 6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation, however its function in ventricular myocardium remains unexplored. Methods and Results We generated multiple cardiac-targeted knock-out mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7-deletion (

Significance T ransient R eceptor P otential M elastatin 7 (TRPM7) is a divalent-permeant channel-kinase of unknown function expressed in human atrial myocytes and fibroblasts and recently implicated in atrial arrhythmias. We show that TRPM7 is highly expressed in embryonic myocardium and sinoatrial node (SAN). Trpm7 disruption in vitro, in cultured embryonic cardiomyocytes, and in vivo in zebrafish and in mice impairs cardiac automaticity. We show that this occurs via reductions in Hcn4 mRNA and the pacemaker current, I f , in SAN. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN via regulation of Hcn4 expression.

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