The dynamics of stochastic attrition viewed as an absorption time on a terminating Markov chain

Abstract

Localized Ca(2+) elevations known as Ca(2+) puffs and sparks are cellular signals that arise from the cooperative activity of clusters of inositol 1,4,5-trisphosphate receptors and ryanodine receptors clustered at Ca(2+) release sites on the surface of the endoplasmic reticulum or sarcoplasmic reticulum. When Markov chain models of these intracellular Ca(2+)-regulated Ca(2+) channels are coupled via a mathematical representation of Ca(2+) microdomain, simulated Ca(2+) release sites may exhibit the phenomenon of "stochastic Ca(2+) excitability" where the inositol 1,4,5-trisphosphate receptors (IP(3)Rs) or ryanodine receptors (RyRs) open and close in a concerted fashion. Interestingly, under some conditions simulated puffs and sparks can be observed even when the single-channel model used does not include slow Ca(2+) inactivation or, indeed, any long-lived closed/refractory state [V. Nguyen, R. Mathias, G. Smith, Stochastic automata network descriptor for Markov chain models of instantaneously-coupled intracellular Ca(2+) channels, Bull. Math. Biol. 67 (2005) 393-432]. In this case, termination of the localized Ca(2+) elevation occurs when all of the intracellular channels at a release site simultaneously close through a process referred to as stochastic attrition [M. Stern, Theory of excitation-contraction coupling in cardiac muscle, Biophys. J. 63 (1992) 497-517]. In this paper, we investigate the statistical properties of stochastic attrition viewed as an absorption time on a terminating Markov chain that represents a Ca(2+) release site composed of N two-state channels that are activated by Ca(2+). Assuming that the local [Ca(2+)] experienced by a channel depends only on the number of open channels at the Ca(2+) release site (i.e., instantaneous mean-field coupling [ibid.], we derive the probability distribution function for the time until stochastic attrition occurs and present an analytical formula for the expectation of this random variable. We explore how the contribution of stochastic attrition to the termination of Ca(2+) puffs and sparks depends on the number of channels at a release site, the source amplitude of the channels (i.e., the strength of the coupling), the background [Ca(2+)], channel kinetics, and the cooperactivity of Ca(2+) binding. Because we explicitly model the Ca(2+) regulation of the intracellular channels, our results differ markedly from (and in fact generalize) preliminary analyses that assume the intracellular Ca(2+) channels are uncoupled and consequently independent.