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

Changes in cytosolic free calcium (Ca(2+)](i)) often take the form of a sustained response or repetitive oscillations. The frequency and amplitude of Ca(2+)](i) oscillations are essential for the selective stimulation of gene expression and for enzyme activation. However, the mechanism that determines whether Ca(2+)](i) oscillates at a particular frequency or becomes a sustained response is poorly understood. We find that Ca(2+)](i) oscillations in rat megakaryocytes, as in other cells, results from a Ca(2+)-dependent inhibition of inositol 1,4,5-trisphosphate (IP(3))-induced Ca(2+) release. Moreover, we find that this inhibition becomes progressively less effective with higher IP(3) concentrations. We suggest that disinhibition, by increasing IP(3) concentration, of Ca(2+)-dependent inhibition is a common mechanism for the regulation of Ca(2+)](i) oscillations in cells containing IP(3)-sensitive Ca(2+) stores.