摘要：Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2 channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2 channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3−/−) or Cav3.1 (Cav3.1−/−) channels and double mutant Cav1.3−/−/Cav3.1−/− mice expressing only Cav1.2 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 Ca2 release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based “Ca2 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.
其他摘要：Abstract 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.
