A mathematical study of the differential effects of two SERCA isoforms on Ca2+ oscillations in pancreatic islets

Cytosolic Ca2+ dynamics are important in the regulation of insulin secretion from the pancreatic beta-cells within islets of Langerhans. These dynamics are sculpted by the endoplasmic reticulum (ER), which takes up Ca2+ when cytosolic levels are high and releases it when cytosolic levels are low. Calcium uptake into the ER is through sarcoendoplasmic reticulum Ca2+-ATPases, or SERCA pumps. Two SERCA isoforms are expressed in the beta-cell: the high Ca2+ affinity SERCA2b pump and the low affinity SERCA3 pump. Recent experiments with islets from SERCA3 knockout mice have shown that the cytosolic Ca2+ oscillations from the knockout islets are characteristically different from those of wild type islets. While the wild type islets often exhibit compound Ca2+ oscillations, composed of fast oscillations superimposed on much slower oscillations, the knockout islets rarely exhibit compound oscillations, but produce slow (single component) oscillations instead. Using mathematical modeling, we provide an explanation for this difference. We also investigate the effect that SERCA2b inhibition has on the model beta-cell. Unlike SERCA3 inhibition, we demonstrate that SERCA2b inhibition has no long-term effect on cytosolic Ca2+ oscillations unless a store-operated current is activated.