Bradycardia and Slowing of the Atrioventricular Conduction in Mice Lacking Ca V 3.1/α 1G T-Type Calcium Channels

Abstract

The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for Ca _v 3.1/α _1G T-type calcium channels ( cacna1g ) abolishes T-type calcium current ( I _Ca,T ) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca ²⁺ current ( I _Ca,L ). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I _Ca,T was detected in right atrium myocytes in both wild-type and Ca _v 3.1 ^−/− mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that Ca _v 3.1/T-type Ca ²⁺ channels contribute to SAN pacemaker activity and atrioventricular conduction.