Spatio-temporal calcium dynamics in pacemaking units of the interstitial cells of Cajal

The interstitial cells of Cajal (ICC) are responsible for producing pacemaking signals that stimulate rhythmic contractions in the gastro-intestinal system. The pacemaking signals are generated by membrane depolarizations, which are in turn linked to the integrated transport of calcium between the endoplasmic reticulum (ER), through inositol-trisphosphate receptor (IP3R) release, and mitochondria, through the uniporter. A non-specific cation channel (NSCC) is associated with the membrane depolarizations, and is inhibited by intracellular calcium. One theory proposes that the integrated calcium transport occurs within specific regions of the ICC called “pacemaker units,” and results in localized calcium concentration reductions within these units, which in turn activate the NSCC and depolarize the membrane. We have constructed a model of the spatio-temporal calcium dynamics within an ICC pacemaker unit to determine under what conditions the local calcium concentrations may reduce below baseline. We obtain reductions of calcium concentrations below baseline but only under certain conditions. Without strong and persistent stimulation of the IP3R, reductions of calcium below baseline occur only with a non-physiological, time-dependent uniporter. Alternatively, sufficient IP3R release leads to reductions of calcium below baseline, due to depletion of the ER calcium store over the time scale of seconds, although these reductions require strong mitochondrial and ER calcium uptake.