The Ion Channel-Kinase, Trpm7, Is Required For 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 calcium-permeant channel-kinase highly expressed in heart, is required for cardiac automaticity, sinoatrial node (SAN) and atrioventricular node (AVN) function. We find larger TRPM7 currents in myocardial cells exhibiting automaticity such as embryonic ventricular myocytes (EVM) and SAN cells, as compared to quiescent adult ventricular myocytes. TRPM7 disruption in cultured EVM reduces spontaneous Ca2+ transient firing rates, impairing automaticity in vitro. Likewise, morpholino mediated TRPM7 knock-down in zebrafish embryo slows heart rate in vivo. Cardiac-targeted TRPM7 deletion in mouse (KO) eliminates TRPM7 current in SAN, inducing episodes of sinus pauses, AVN block and cardiomyopathy. Freshly isolated SAN from KO mice exhibit diminished Ca2+ transient firing rates and a blunted diastolic Ca2+ rise. Moreover, action potential firing rates are diminished in KO SAN due to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, If, are diminished in both SAN and AVN from KO mice. We conclude that TRPM7 both regulates Hcn4 expression and provides a novel, previously unrecognized diastolic Ca2+ current at hyperpolarized membrane potentials, each contributing to diastolic membrane depolarization and myocardial automaticity in SAN and AVN.