Role of the Inter-RyR Coupling in Cardiac Intracellular Calcium “Clock”

Abstract

Cardiac rhythm is generated by the sinoatrial node in the normal heart. It has been recently shown that spontaneous local Ca2+ releases from sarcoplasmic reticulum (SR) through Ryanodine Receptors (RyRs) occur during late diastolic depolarization and may contribute to the periodic excitations of pacemaker cells [Vinogradova et al., Circ. Res. 02]. Such intracellular Ca2+ oscillations, referred to as Ca2+-“clock” [Maltsev, Lakatta, Am J Physiol Heart Circ Physiol, 2009], interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na2+-Ca2+ exchange current.We developed an Electron-Conformational Model (ECM) of the stochastic RyR-channel activity, which accounted for cooperative effects of interaction between coupled RyR-channels within a Ca2+ release unit (RU) in cardiac pacemaker cells [Moskvin et al., PBMB 2006]. The RU includes a junctional Ca2+ release compartment of the SR network, a cluster of coupled RyR-channels, and adjacent sarcolemmal subspace. Inter-channel conformational coupling between nearest RyR neighbors is accounted for the energy potential of the cluster. The RU activity is described along with intracellular Ca2+ cycling between the subspace, cytosol, and the SR network.Computer simulations of a 9x9 RyR square lattice within the framework of ECM demonstrate that the Ca2+ SR “clock” activity is regulated by the interaction between RyR channels. Stability of oscillatory dynamics, frequency and amplitude of Ca2+ auto-oscillations depend essentially on the RyRs coupling force. We found that a combination of rather low Ca2+ release rate with strong enough RyR-RyR coupling may trigger sudden break of Ca2+ oscillations by forming of stable clusters of opened RyRs and thus providing with the steady-state Ca2+ leakage from the SR.Supported by Grants 12-П-4-1067, 12-04-32059-МОЛ_A_2013, 11-4-НП-673.