Calcium oscillation frequency-sensitive gene regulation and homeostatic compensation in Pancreatic Beta Cells

Pancreatic islet β -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 Ca ^{2 +} oscillations that accompany bursting electrical activity of β -cells and are physiologically important. ATP-sensitive K ⁺ 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, β -cells fail to respond appropriately to changes in the blood glucose level, and electrical and Ca ^{2 +} oscillations are lost. However, mice compensate for K(ATP) channel defects in islet β -cells by employing alternative mechanisms to maintain electrical and Ca ^{2 +} oscillations. In a recent study, we showed that in mice islets in which K(ATP) channels are genetically knocked out another K ⁺ current, provided by inward-rectifying K ⁺ channels, is increased. With mathematical modeling, we demonstrated that a sufficient upregulation in these channels can account for the paradoxical electrical bursting and Ca ^{2 +} oscillations observed in these β -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. Ca ^{2 +} is a well-known regulator of gene expression, and several examples have been shown of genes that are sensitive to the frequency of the Ca ^{2 +} signal. In this mathematical modeling study, we demonstrate that a Ca ^{2 +} oscillation frequency-sensitive gene transcription network can adjust the gene expression level of a compensating K ⁺ channel so as to rescue electrical bursting and Ca ^{2 +} oscillations in a model β -cell in which the key K(ATP) current is removed. This is done without the prescription of a target Ca ^{2 +} level, but evolves naturally as a consequence of the feedback between the Ca ^{2 +}-dependent enzymes and the cell’s electrical activity. More generally, the study indicates how Ca ^{2 +} can provide the link between gene expression and cellular electrical activity that promotes wild-type behavior in a cell following gene knockout.