Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function

摘要

For almost half a century it has been thought that the initiation of each heartbeat is driven by surface membrane voltage-gated ion channels (M clocks) within sinoatrial nodal cells. It has also been assumed that pacemaker cell automaticity is initiated at the maximum diastolic potential (MDP). Recent experimental evidence based on confocal cell imaging and supported by numerical modelling, however, shows that initiation of cardiac impulse is a more complex phenomenon and involves yet another clock that resides under the sarcolemma. This clock is the sarcoplasmic reticulum (SR): it generates spontaneous, but precisely timed, rhythmic, submembrane, local Ca2+ releases (LCR) that appear not at the MDP but during the late, diastolic depolarization (DD). The Ca2+ clock and M clock dynamically interact, defining a novel paradigm of robust cardiac pacemaker function and regulation. Rhythmic LCRs during the late DD activate inward Na+/Ca2+ exchanger currents and ignite action potentials, which in turn induceCa2+ transients and SR depletions, resetting the Ca2+ clock. Both basal and reserve protein kinaseA-dependent phosphorylation of Ca2+ cycling proteins control the speed and amplitude of SR Ca2+ cycling to regulate the beating rate by strongly coupled Ca2+ and M clocks.