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

TL;DR

This paper models elementary Ca sparks in cardiac cells as a transition of a release channel system from a metastable to an active state, using a Markov chain and Ising model formalism to explain spark initiation.

Contribution

It introduces a novel system-level model of Ca spark activation as a metastable state transition, providing mechanistic insights and quantitative predictions.

Findings

Model reproduces experimental Ca spark thresholds.

Predicts spark probability as a function of Ca concentration.

Aligns with observed spark activation behavior in cardiac cells.

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.