Spatial Imperfection Encodes Functional Perfection: Success and Failure of Calcium Release to Propagate Regulate Pacemaker Cell Function

Abstract

Local Diastolic Ca2+releases (LCRs) contribute to sinoatrial-node-cell pacemaker function by activation of Na+/Ca2+exchanger current that accelerates diastolic depolarization. LCRs are generated by clusters of ryanodine receptors, Ca2+release units (CRUs), residing in the sarcoplasmic reticulum. CRU distribution in pacemaker cells exhibits substantial heterogeneity vs. a crystal-like distribution of cardiac muscle cells. While this heterogeneity can be noticed in images of ryanodine receptor immunofluorescence, its functional importance has never been addressed. We approached the problem by performing numerical simulations in a new sinoatrial-node-cell model that has membrane ion currents and a sub-membrane sarcoplasmic reticulum with a Ca2+pump and two-dimensional array of stochastic, diffusively coupled CRUs. With an equally-spaced, crystal-like distribution of CRUs, synchronization of Ca2+releases during diastolic depolarization undergoes an explosive, phase-like transition from individual Ca2+sparks to simultaneous occurrence of merging numerous LCRs over the entire cell, i.e. an all-or-none behavior. Since almost all CRUs fire during the phase transition (leaving no reserve), the model is not amenable to autonomic modulation of pacemaker rate. Allowing each CRU position to vary around its original crystalline position fundamentally changes the model behavior: the transition from individual sparks to propagating LCRs becomes smooth with the number and sizes of LCRs observed experimentally. Furthermore, some distant CRUs do not fire during diastolic depolarization under resting conditions, but become engaged (as a reserve) during beta-adrenergic stimulation. Thus, the model with the CRU positional variability is easily tuned to respond to autonomic modulation. We conclude: the irregularity in CRU distribution in sinoatrial-node-cells is not a noise or imperfection, but rather a functional modality of the pacemaker cells that allows them to gradually engage CRUs to satisfy the chronotropic demand of the heart at a given condition.