ABSTRACT
An integrative model of the calcium dynamics in cardiac pacemaker cells is developed taking into account a synergetic effect of the interaction between an outer membrane oscillator and an intracellular calcium oscillator ("membrane and Ca(2+)-clock"). The main feature of the model is a description of the stochastic dynamics of Ca2+ release units within the electron-conformational mechanism of the functioning of ryanodine-sensitive calcium channels. It is shown that interaction of two cellular oscillators provides a stable action potential generation in the cardiac pacemaker cells even in the case of the stochastic Ca2+ dynamics. We studied in detail the effect of ryanodine channels sensitivity to an increase in the intracellular calcium concentration in sarcoplasmic reticulum and in the dyadic space on the behavior of calcium-release system. A parametric analysis of the integrative model of pacemaker cells is performed.
Subject(s)
Calcium/metabolism , Myocytes, Cardiac/metabolism , Pacemaker, Artificial , Ryanodine Receptor Calcium Release Channel/chemistry , Action Potentials , Animals , Biological Clocks , Calcium/chemistry , Calcium Signaling/physiology , Membranes/chemistry , Membranes/metabolism , Models, Theoretical , Myocytes, Cardiac/chemistry , Ryanodine Receptor Calcium Release Channel/metabolismSubject(s)
Heart Ventricles/pathology , Adult , Diastole , Echocardiography/methods , Female , Fourier Analysis , Heart , Heart Septum/pathology , Humans , Infant, Newborn , Male , Models, Anatomic , Models, Theoretical , Morphogenesis , SystoleABSTRACT
We propose a simple, physically reasonable electron-conformational model for the ryanodine receptor (RyR) and, on that basis, present a theory to describe RyR lattice responses to L-type channel triggering as an induced non-equilibrium phase transition. Each RyR is modelled with a single open and a single closed (electronic) state only, described utilizing a s=12 pseudospin approach. In addition to the fast electronic degree of freedom, the RyR channel is characterized by a slow classical conformational coordinate, Q, which specifies the RyR channel calcium conductance and provides a multimodal continuum of possible RyR states. The cooperativity in the RyR lattice is assumed to be determined by inter-channel conformational coupling. Given a threshold sarcoplasmic reticulum (SR) calcium load, the RyR lattice fires due to a nucleation process with a step-by-step domino-like opening of a fraction of lattice channels, providing for a sufficient release to generate calcium sparks. The optimal mode of RyR lattice functioning during calcium-induced calcium release implies a fractional release with a robust termination due to a decrease in SR calcium load, accompanied by a respective change in effective conformational strain of the lattice. SR calcium overload is shown to result in excitation of RyR lattice auto-oscillations with spontaneous RyR channel opening and closure.
