Role of the Plasma Membrane Ca 2+ -ATPase Pump in the Regulation of Rhythm Generation by an Interstitial Cell of Cajal: A Computational Study

Gastrointestinal motility is based on the rhythmic activity of interstitial cells of Cajal (ICCs). The ICC rhythm generation relies upon characteristic Ca 2+ -handling mechanisms that involve voltage-gated Ca 2+ channels, pumps and exchangers located in the plasma membrane, endoplasmic reticulum (ER), and mitochondria. Mutations, overexpression, and genetic knockdowns of the plasma membrane calcium ATPase (PMCA) pumps have been shown to disrupt calcium signaling and to cause disorders in other cell systems. Using an ICC biophysical model, we investigated the effects of PMCA pump upregulation in ICC rhythm generation. We found that, depending on the PMCA maximum pumping rate, the ICC model generates voltage and Ca 2+ oscillations with different characteristics or becomes silent. The model predicts the coexistence of activity regimes near a canonical set of the parameters. One of these regimes is a silent regime that would indicate gastric dysmotility.