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.