Elementary Intracellular Ca Signals are Initiated by a Transition of Release Channel System from a Metastable State

Abstract: Cardiac muscle contraction is initiated by an elementary Ca signal (called Ca spark) which is achieved by collective action of Ca release channels in a cluster. The mechanism of this synchronization remains uncertain. This paper approaches Ca spark activation as an emergent phenomenon of an interactive system of release channels. We construct a Markov chain that applies an Ising model formalism to such release channel clusters and realistic open channel configurations to demonstrate that spark activation is described as a system transition from a metastable to an absorbing state, analogous to the pressure required to overcome surface tension in bubble formation. This yields quantitative estimates of the spark generation probability as a function of various system parameters. Our model of the release channel system yields similar results for the sarcoplasmic reticulum Ca concentration threshold for spark activation as previous experimental results, providing a mechanistic explanation of the spark initiation. Additionally, we perform numerical simulations to find spark probabilities as a function of sarcoplasmic reticulum Ca concentration obtaining similar values for spark activation threshold as our analytic model, as well as those reported in experimental studies.