A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

Classical numerical models have attributed the regulation of normal cardiac automaticity in sinoatrial node cells (SANCs) largely to G protein-coupled receptor (GPCR) modulation of sarcolemmal ion currents. More recent experimental evidence, however, has indicated that GPCR modulation of SANCs automaticity involves spontaneous, rhythmic, local [Ca.sup.2+] releases (LCRs) from the sarcoplasmic reticulure (SR). We explored the GPCR rate modulation of SANCs using a unique and novel numerical model of SANCs in which [Ca.sup.2+]-release characteristics are graded by variations in the SR [Ca.sup.2+] pumping capability, mimicking the modulation by phospholamban regulated by cAMP-mediated, PKA-activated signaling. The model faithfully predicted the entire range of physiological chronotropic modulation of SANCs by the activation of [beta]-adrenergic receptors or cholinergic receptors only when experimentally documented changes of sarcolemmal ion channels are combined with a simultaneous increase/ decrease in SR [Ca.sup.2+] pumping capability. The novel numerical mechanism of GPCR rate modulation is based on numerous complex synergistic interactions between sarcolemmal and intracellular processes via membrane voltage and [Ca.sup.2+]. Major interactions include changes of diastolic [Na.sup.+]/[Ca.sup.2+] exchanger current that couple earlier/ later diastolic [Ca.sup.2+] releases (predicting the experimentally defined LCR period shill) of increased/decreased amplitude (predicting changes in LCR signal mass, i.e, the product of LCR spatial size. amplitude, and number per cycle) to the diastolic depolarization and ultimately to the spontaneous action potential firing rate. Concomitantly, larger/smaller and more/less frequent activation of L-type [Ca.sup.2+] current shifts the cellular [Ca.sup.2+] balance to support the respective [Ca.sup.2+] cycling changes. In conclusion, our model simulations corroborate recent experimental results in rabbit SANCs pointing to a new paradigm for GPCR heart rate modulation by a complex system of dynamically coupled sarcolemmal and intracellular proteins. calcium; sarcoplasmic reticulum; ion channels; numerical modeling; sinoatrial node cell doi: 10.1152/ajpheart.00783.2009.