A Mathematical Study of the Differential Effects of Two SERCA Isoforms on Calcium Oscillations in Pancreatic Islets

R. Rertram and Rudy C. Arceo II

Cytosolic calcium 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 calcium when cytosolic levels are high and releases it when cytosolic levels are low. Calcium uptake into the ER is through sarcoendoplasmic reticulum calcium-ATPases, or SERCA pumps. Two SERCA isoforms are expressed in the beta-cell: the high calcium affinity SERCA2b pump and the low affinity SERCA3 pump. Recent experiments with islets from SERCA3 knockout mice have shown that the cytosolic calcium oscillations from the knockout islets are characteristically different from those of wild type islets. While the wild type islets often exhibit compound calcium 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 calcium oscillations unless a store-operated current is activated.