Calcium Oscillation Frequency-Sensitive Gene Regulation and Homeostatic Compensation in Pancreatic beta-Cells

Vehpi Yildirim, Richard Bertram

Pancreatic islet beta-cells are electrically excitable cells that secrete insulin in an oscillatory fashion when the blood glucose concentration is at a stimulatory level. Insulin oscillations are the result of cytosolic calcium oscillations that accompany bursting electrical activity of beta-cells, and are physiologically important. ATP sensitive potassium channels (K(ATP) channels) play the key role in setting the overall activity of the cell and in driving bursting, by coupling cell metabolism to the membrane potential. In humans, when there is a defect in K(ATP) channel function beta-cells fail to respond appropriately to changes in the blood glucose level, and electrical and calcium oscillations are lost. However, mice compensate for K(ATP) channel defects in islet beta-cells by employing alternative mechanisms to maintain electrical and calcium oscillations. In a recent study, we showed that in mice islets in which K(ATP) channels are genetically knocked out another potassium current, provided by inward-rectifying potassium channels, is increased. With mathematical modeling, we demonstrated that a sufficient upregulation in these channels can account for the paradoxical electrical bursting and calcium oscillations observed in these beta-cells. However, the question of determining the correct level of upregulation that is necessary for this compensation remained unanswered, and this question motivates the current study. Calcium is a well-known regulator of gene expression and several examples have been shown of genes that are sensitive to the frequency of the calcium signal. In this mathematical modeling study, we demonstrate that a calcium oscillation frequency sensitive gene transcription network can adjust the gene expression level of a compensating potassium channel so as to rescue electrical bursting and calcium oscillations in a model beta-cell in which the key K(ATP) current is removed. This is done without the prescription of a target calcium level, but evolves naturally as a consequence of the feedback between the calcium-dependent enzymes and the cell's electrical activity. More generally, the study indicates how calcium can provide the link between gene expression and cellular electrical activity that promotes wild-type behavior in a cell following gene knockout.