Dual regulation of calcium mobilization by inositol 1,4, 5-trisphosphate in a living cell.

Changes in cytosolic free calcium ([Ca2+](i)) often take the form of a sustained response or repetitive oscillations. The frequency and amplitude of [Ca2+](i) oscillations are essential for the selective stimulation of gene expression and for enzyme activation. However, the mechanism that determines whether [Ca2+](i) oscillates at a particular frequency or becomes a sustained response is poorly understood. We find that [Ca2+](i) oscillations in rat megakaryocytes, as in other cells, results from a Ca2+-dependent inhibition of inositol 1,4,5-trisphosphate (IP3)induced Ca2+ release. Moreover, we find that this inhibition becomes progressively less effective with higher IP3 concentrations. We suggest that disinhibition, by increasing IP3 concentration, of Ca2+-dependent inhibition is a common mechanism for the regulation of [Ca2+](i) oscillations in cells containing IP3-sensitive Ca2+ stores.