Concomitant genetic ablation of L-type Ca1.3 (α) and T-type Ca3.1 (α) Ca channels disrupts heart automaticity.

Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Ca1.2 Ca channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Ca1.3 and T-type Ca3.1 Ca channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Ca1.3 (Ca1.3) or Ca3.1 (Ca3.1) channels and double mutant Ca1.3/Ca3.1 mice expressing only Ca1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart automaticity and define an integral role for these channels in mechanisms that control the heartbeat.