The Beat Goes On

Abstract

See related article, pages 979–987 In this issue Bogdanov et al1 show how late diastolic depolarization in rabbit SA-node pacemaker (SAN) cells may be driven largely by stochastic local SR Ca2+ release events (LCRs), consequent pulses of inward Na/Ca2+ exchange current ( I NCX) and small jumps in membrane potential (Em). This group has published a comprehensive series of studies (see their reference list) and have made a compelling case for the importance of SR Ca2+ release in SAN pacemaker rate, and response to β-adrenergic activation. The mechanism is as follows (Figure 1). SAN cells have relatively high basal levels of cAMP and phospholamban phosphorylation,2 resulting in highly active SR Ca2+ uptake. After a prior beat, as SR Ca2+ content rises and the ryanodine receptor (RyR) recovers its triggerability, the high luminal [Ca2+] causes activation of a cluster of RyRs to produce an LCR or Ca2+ spark. The rise in local [Ca2+]i near the Na/Ca2+ exchanger activates Ca2+ extrusion via inward I NCX causing depolarization. In particular, these Ca sparks (or LCRs) are known to be very brief stochastic local releases of a bolus of Ca2+, which induce an almost simultaneous bolus of inward I NCX (because of the high local submembrane [Ca2+]i near the NCX).3 Note the simultaneous spikes on the RyR release and I NCX traces in Figure 2. The high membrane impedance of SAN cells (because of minimal inward rectifier K current I K1)4 allows this brief pulse of inward current to cause a small jump in Em. As more and more of these stochastic events occur during late diastole the diastolic depolarization steepens, bringing Em to the threshold …