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.