Biophysical re-equilibration of Ca2+ fluxes as a simple biologically plausible explanation for complex intracellular Ca2+ release patterns

Physiological regulation of Ca2+ release from the endoplasmic reticulum (ER) is critical for cell function. Recent direct measurements of free [Ca2+] inside the ER ([Ca2+]ER) revealed that [Ca2+]ER itself is a key regulator of ER Ca2+ handling. However, the role of this new regulatory process in generating various patterns of Ca2+ release remains to be elucidated in detail. Here, we incorporate the recently quantified experimental correlations between [Ca2+]ER and Ca2+ movements across the ER membrane into a mathematical model ER Ca2+ handling. The model reproduces basic experimental dynamics of [Ca2+]ER. Although this was not goal in model design, the model also exhibits mechanistically unclear experimental phenomena such as “quantal” Ca2+ release, and “store charging” by increasing resting cytosolic [Ca2+]. While more complex explanations cannot be ruled out, on the basis of our data we propose that “quantal release” and “store charging” could be simple re-equilibration phenomena, predicted by the recently quantified biophysical dynamics of Ca2+ movements across the ER membrane.