Electron-Conformational Model of SR-Based Ca2+ Clock Mode

Abstract

Most of the calcium that activates cardiac contraction comes from the sarcoplasmic reticulum (SR) from where it is released through the Ryanodine Receptors (RyRs). It is well known that the SR overload results in the release of Ca from the SR in the form of waves driving some cardiac arrhythmias. Recently it has been experimentally documented that the isolated SR is capable to spontaneously and rhythmically release Ca2+ (SR-based Ca2+ clock). This self-sustained intracellular Ca2+ oscillator contributes substantially to the late phase of the diastolic depolarization of cardiac pacemaker cells under normal physiological conditions. Interaction of “a surface membrane oscillator” and “an internal oscillator” with “cycles of Ca2+ uptake and release by the SR” can drive normal cardiac automaticity. To describe the SR-based Ca2+ clock mode we propose a simple, physically-reasonable electron-conformational (EC) model for the RyR and present a theory to describe the RyR lattice dynamics. Each RyR is modelled with a single open and closed electronic state. In addition to the fast electronic degree of freedom, RyR channels are characterized by a slow classical conformational coordinate, which specifies the RyR channel conductance. The RyR gating implies a conformational Langevin dynamics, Ca2+-induced electronic transitions, quantum tunneling and thermal transitions. The cooperativity in the RyR lattice is assumed to be determined by the inter-channel conformational coupling. Model simulations of the of 11x11 RyR cluster revealed different regimes depending on the cis- and trans-Ca concentrations and parameters of EC-model. The SR overload is shown to result in RyR lattice auto-oscillations with spontaneous RyR channel openings and closures. We have studied this Ca2+ clock mode, in particular, its stability, under different model suggestions as regards the RyR conformational potential (diabatic and adiabatic regimes), EC-model parameters.Supported by the RFBR 07-04-96126