Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity

Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca2+ transient firing rates and is associated with robust down-regulation of Hcn4, Ca(v)3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO alpha MHC-Cre), and tamoxifen-inducible SAN restricted Trpm7 deletion (KOHCN4-CreERT2) disrupts cardiac automaticity in vivo. Telemetered and sedated KO alpha MHC-Cre and KOHCN4-CreERT2 mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO alpha MHC-Cre mice exhibit diminished Ca2+ transient firing rates with a blunted diastolic increase in Ca2+. Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, I-f, are diminished in SAN from both KO alpha MHC-Cre and KOHCN4-CreERT2 mice. Moreover, heart rates of KO alpha MHC-Cre mice are less sensitive to the selective I-f blocker ivabradine, and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression.