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

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