Cav1.3 channels in mouse sinoatrial node cells exhibit unique voltage-dependent facilitation and colocalization with ryanodine receptors, which may play a specific role in opposing abnormal slowing of heart rate.
Key points In the sinoatrial node (SAN), Ca v 1 voltage‐gated Ca 2+ channels mediate L‐type currents that are essential for normal cardiac pacemaking. Both Ca v 1.2 and Ca v 1.3 Ca 2+ channels are expressed in the SAN but how their distinct properties affect cardiac pacemaking is unknown. Here, we show that unlike Ca v 1.2, Ca v 1.3 undergoes voltage‐dependent facilitation and colocalizes with ryanodine receptors in sarcomeric structures. By mathematical modelling, these properties of Ca v 1.3 can improve recovery of pacemaking after pauses and stabilize SAN pacemaking during excessively slow heart rates. We conclude that voltage‐dependent facilitation and colocalization with ryanodine receptors distinguish Ca v 1.3 from Ca v 1.2 channels in the SAN and contribute to the major impact of Ca v 1.3 on pacemaking. Abstract Dysregulation of L‐type Ca 2+ currents in sinoatrial nodal (SAN) cells causes cardiac arrhythmia. Both Ca v 1.2 and Ca v 1.3 channels mediate sinoatrial L‐type currents. Whether these channels exhibit differences in modulation and localization, which could affect their contribution to pacemaking, is unknown. In this study, we characterized voltage‐dependent facilitation (VDF) and subcellular localization of Ca v 1.2 and Ca v 1.3 channels in mouse SAN cells and determined how these properties of Ca v 1.3 affect sinoatrial pacemaking in a mathematical model. Whole cell Ba 2+ currents were recorded from SAN cells from mice carrying a point mutation that renders Ca v 1.2 channels relatively insensitive to dihydropyridine antagonists. The Ca v 1.2‐mediated current was isolated in the presence of nimodipine (1 μ m ), which was subtracted from the total current to yield the Ca v 1.3 component. With strong depolarizations (+80 mV), Ca v 1.2 underwent significantly stronger inactivation than Ca v 1.3. VDF of Ca v 1.3 was evident during recovery from inactivation at a time when Ca v 1.2 remained inactivated. By immunofluorescence, Ca v 1.3 colocalized with ryanodine receptors in sarcomeric structures while Ca v 1.2 was largely restricted to the delimiting plasma membrane. Ca v 1.3 VDF enhanced recovery of pacemaker activity after pauses and positively regulated pacemaking during slow heart rate in a numerical model of mouse SAN automaticity, including preferential coupling of Ca v 1.3 to ryanodine receptor‐mediated Ca 2+ release. We conclude that strong VDF and colocalization with ryanodine receptors in mouse SAN cells are unique properties that may underlie a specific role for Ca v 1.3 in opposing abnormal slowing of heart rate.
Christel et al. (Tue,) studied this question.