Normal automaticity in sinoatrial node cells (SANC) involves intracellular Ca2+ cycling within a coupled-clock system: periodic local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (Ca2+ clock) activate an inward Na+-Ca2+ exchange current that accelerates the diastolic depolarization prompting the ensemble of surface membrane ion channels (membrane clock) to generate the next action potential (AP). Whether intracellular Ca2+ regulates SANC AP firing rate on a beat-to-beat basis is controversial. We loaded single isolated SANC with a caged Ca2+ buffer, NP-EGTA, and simultaneously recorded membrane potential and intracellular Ca2+. Prior to introduction of the caged Ca2+ buffer, spontaneous LCRs during diastolic depolarization (DD) were tightly coupled to rhythmic APs (r2=0.9). The buffer markedly prolonged the decay time (T50) of the AP-induced Ca2+ transient and partially depleted the SR load level, suppressed spontaneous diastolic LCRs and uncoupled them from AP generation, and caused AP firing to become markedly slow and dysrhythmic. When Ca2+ was acutely released from the caged compound by flash photolysis, intracellular Ca2+ dynamics were acutely restored and rhythmic APs resumed immediately at a normal rate. After a few rhythmic cycles, however, these effects of the flash waned as interference with Ca2+ dynamics by the caged buffer was reestablished. Our results directly support the hypothesis that a system of an intracellular Ca2+ clock coupled to a surface membrane voltage clock regulates normal SANC automaticity on a beat-to-beat basis. We investigated recently whether a change in beating rate (i.e., due to autonomic receptor stimulation) is accompanied by rhythm variation (beat-to-beat variability in rate). Autonomic receptor stimulations affected both the beating rate and rhythm variability in isolated rabbit pacemaker cells;i.e. decrease in beating rate occurred concurrently with increase in rhythm variability. Under physiological conditions, application of low concentrations of caffeine (2-4mM) to isolated single rabbit SANC acutely reduces their spontaneous action potential cycle length (CL) and increases Ca2+ transient amplitude for several cycles. Numerical simulations, using a modified Maltsev-Lakatta coupled-clock model, faithfully reproduced these effects, and also the effects of CL prolongation and dys-rhythmic spontaneous beating produced by cytosolic Ca2+ buffering and an acute CL reduction produced by flash-induced Ca2+ release from a caged Ca2+ buffer, that we had reported previously. Three contemporary numerical models (including the original Maltsev-Lakatta model) failed to reproduce the experimental results. In our new model, Ca2+ releases acutely change the CL via activation of the Na+/Ca2+ exchanger current. Time-dependent cycle length reductions after flash-induced Ca2+ releases (memory effect) are linked to changes in Ca2+ available for pumping into sarcoplasmic reticulum which, in turn, changes the sarcoplasmic reticulum Ca2+ load, diastolic Ca2+ releases and Na+/Ca2+ exchanger current. These results support the idea that Ca2+ regulates CL in cardiac pacemaker cells on a beat-to-beat basis, and suggest a more realistic numerical mechanism of this regulation.

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Sirenko, Syevda G; Maltsev, Victor A; Yaniv, Yael et al. (2016) Electrochemical Na+ and Ca2+ gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells. Am J Physiol Heart Circ Physiol 311:H251-67
Yaniv, Yael; Lakatta, Edward G (2015) The end effector of circadian heart rate variation: the sinoatrial node pacemaker cell. BMB Rep 48:677-84
Yaniv, Yael; Tsutsui, Kenta; Lakatta, Edward G (2015) Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing. Front Physiol 6:47
Yaniv, Yael; Lakatta, Edward G; Maltsev, Victor A (2015) From two competing oscillators to one coupled-clock pacemaker cell system. Front Physiol 6:28
Yaniv, Yael; Lyashkov, Alexey E; Lakatta, Edward G (2014) Impaired signaling intrinsic to sinoatrial node pacemaker cells affects heart rate variability during cardiac disease. J Clin Trials 4:
Yaniv, Yael; Ahmet, Ismayil; Liu, Jie et al. (2014) Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals. Heart Rhythm 11:1210-9
Maltsev, Victor A; Yaniv, Yael; Maltsev, Anna V et al. (2014) Modern perspectives on numerical modeling of cardiac pacemaker cell. J Pharmacol Sci 125:6-38
Liu, Jie; Sirenko, Syevda; Juhaszova, Magdalena et al. (2014) Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling. Am J Physiol Heart Circ Physiol 306:H1385-97
Yaniv, Yael; Lakatta, Edward G (2013) Pacemaker gene mutations, bradycardia, arrhythmias and the coupled clock theory. J Cardiovasc Electrophysiol 24:E28-9
Yaniv, Yael; Stern, Michael D; Lakatta, Edward G et al. (2013) Mechanisms of beat-to-beat regulation of cardiac pacemaker cell function by Ca²⁺ cycling dynamics. Biophys J 105:1551-61

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