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Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Ca v 1.2 Ca 2+  channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Ca v 1.3 and T-type Ca v 3.1 Ca 2+  channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Ca v 1.3 ( Ca   v   1.3   −/ − ) or Ca v 3.1 ( Ca   v   3.1   −/ − ) channels and double mutant  Ca   v   1.3   −/ − / Ca   v   3.1   −/ −  mice expressing only Ca v 1.2 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 2+  release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based “ Ca   2 +   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.

Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity