Interplay of Membrane and Calcium Oscillators in Cardiac Pacemaker Cells

Abstract

Recently it has been shown [Maltsev, Lakatta, Am J Physiol Heart Circ Physiol, 2009] that a stable calcium oscillatory dynamics in cardiac pacemaker cells is developed due to a synergetic effect of the coupling of the classic sarcolemmal voltage oscillator (“membrane” clock) and the intracellular calcium oscillator, or “Ca2+-clock”, whose functioning is governed by the ryanodine (RyR) channel gating. At variance with the Maltsev-Lakatta approach we developed an integrative model of coupled cellular oscillators using a simple electron-conformational theory [Moskvin et al., PBMB, 2006] to describe the stochastic RyR gating in a Ca2+ release unit (RU). The RU includes a junctional compartment of the sarcoplasmic reticulum (SR) network, a cluster of coupled RyR-channels, and adjacent sarcolemmal subspace (SS). The RU activity implies an intracellular Ca2+ cycling between the compartments. Computer simulations demonstrate that despite a stochastic Ca2+ dynamics the coupling of the cellular oscillators can provide a stable action potential generation in the cardiac pacemaker cells, however, with clear signatures of “micro-arrhythmia”, that is the fluctuations of the frequency and amplitude of the Ca2+ release. We studied in detail the effect of “funny” current and of the RyRs’ sensitivity to the [CaSR] and [CaSS] on the behavior of the calcium release system. A parametric analysis shows that depending on the model parameters either the membrane or Ca2+-clock actually plays the leading role providing the astonishing stability of the auto-oscillatory regime. At the same time, the inter-RyR coupling is shown to strongly influence the stability up to manifestation of the puzzling sudden break of Ca2+ oscillations. Supported by the Russian Science Foundation, project 14-35-00005.