Concomitant genetic ablation of L-type Ca v 1.3 (α 1D ) and T-type Ca v 3.1 (α 1G ) Ca 2+ 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 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.