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

ABSTRACT

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.