Key result
A novel numerical model of sinoatrial node cells predicted physiological chronotropic modulation by beta-adrenergic or cholinergic receptors only when changes in sarcolemmal ion channels were combined with simultaneous changes in sarcoplasmic reticulum calcium pumping capability.
A novel numerical model demonstrates that GPCR heart rate modulation in sinoatrial node cells relies on dynamically coupled sarcolemmal and intracellular proteins, including SR Ca(2+) pumping.
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(2+) releases (LCRs) from the sarcoplasmic reticulum (SR). We explored the GPCR rate modulation of SANCs using a unique and novel numerical model of SANCs in which Ca(2+)-release characteristics are graded by variations in the SR Ca(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(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(2+). Major interactions include changes of diastolic Na(+)/Ca(2+) exchanger current that couple earlier/later diastolic Ca(2+) releases (predicting the experimentally defined LCR period shift) 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(2+) current shifts the cellular Ca(2+) balance to support the respective Ca(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.
No takes yet. Share an insight, caveat, or question.
Maltsev et al. (2010) studied Cardiac pacemaker cell automaticity. Beta-adrenergic and cholinergic receptor stimulation (numerical model) vs. Basal state model was evaluated on Spontaneous action potential firing rate. A novel numerical model of sinoatrial node cells predicted physiological chronotropic modulation by beta-adrenergic or cholinergic receptors only when changes in sarcolemmal ion channels were combined with simultaneous changes in sarcoplasmic reticulum calcium pumping capability.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: