Local control of Ca²⁺-induced Ca²⁺ release in mouse sinoatrial node cells

Emerging evidence from large animal models implicates Ca²⁺ regulation, particularly intracellular sarcoplasmic reticulum (SR) Ca²⁺ release, as essential for sinoatrial node (SAN) automaticity. However, despite the apparent importance of SR Ca²⁺ release to SAN cell function it is uncertain how SR Ca²⁺ release is controlled in SAN cells from mouse. Understanding mouse SAN SR Ca²⁺ release mechanism will allow improved understanding of results in studies on SAN from genetic mouse models of Ca²⁺ homeostatic proteins. Here we investigated the functional relationship between sarcolemmal Ca²⁺ influx and SR Ca²⁺ release at the level of single SAN cell, using simultaneous patch-clamp current recording and high resolution confocal Ca²⁺ imaging techniques. In mouse SAN cells, both Ca²⁺ channel currents and triggered SR Ca²⁺ transients displayed bell-shaped, graded function with the membrane potential. Moreover, the gain function for Ca²⁺-induced Ca²⁺ release (CICR) displayed a monotonically decreasing function with strong voltage dependence, consistent with a "local control" mechanism for CICR. In addition, we observed numerous discrete Ca²⁺ sparks at the voltage range of diastolic depolarization, in sharp contrast to the much lower frequency of sparks observed at resting potentials. We concluded that the "local control" mechanism of CICR is responsible for both local Ca²⁺ release during diastolic depolarization and the synchronized Ca²⁺ transients observed during action potential in SAN cells.