Calcium-dependent inactivation and the dynamics of calcium puffs and sparks.

Localized intracellular Ca(2+) elevations known as puffs and sparks arise from the cooperative activity of inositol 1,4,5-trisphosphate receptor Ca(2+) channels (IP(3)Rs) and ryanodine receptor Ca(2+) channels (RyRs) 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 a Ca(2+) microdomain, simulated Ca(2+) release sites may exhibit the phenomenon of "stochastic Ca(2+) excitability" reminiscent of Ca(2+) puffs and sparks where channels open and close in a concerted fashion. To clarify the role of Ca(2+) inactivation of IP(3)Rs and RyRs in the dynamics of puffs and sparks, we formulate and analyze Markov chain models of Ca(2+) release sites composed of 10-40 three-state intracellular Ca(2+) channels that are inactivated as well as activated by Ca(2+). We study how the statistics of simulated puffs and sparks depend on the kinetics and dissociation constant of Ca(2+) inactivation and find that puffs and sparks are often less sensitive to variations in the number of channels at release sites and strength of coupling via local [Ca(2+)] when the average fraction of inactivated channels is significant. Interestingly, we observe that the single channel kinetics of Ca(2+) inactivation influences the thermodynamic entropy production rate of Markov chain models of puffs and sparks. While excessively fast Ca(2+) inactivation can preclude puffs and sparks, moderately fast Ca(2+) inactivation often leads to time-irreversible puffs and sparks whose termination is facilitated by the recruitment of inactivated channels throughout the duration of the puff/spark event. On the other hand, Ca(2+) inactivation may be an important negative feedback mechanism even when its time constant is much greater than the duration of puffs and sparks. In fact, slow Ca(2+) inactivation can lead to release sites with a substantial fraction of inactivated channels that exhibit puffs and sparks that are nearly time-reversible and terminate without additional recruitment of inactivated channels.