Of all the intracellular organelles, secretory granules contain by far the highest calcium concentration; secretory granules of typical neuroendocrine chromaffin cells contain approximately 40 mM Ca(2+) and occupy approximately 20% cell volume, accounting for >60% of total cellular calcium. They also contain the majority of cellular inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in addition to the presence of >2 mM of chromogranins A and B that function as high-capacity, low-affinity Ca(2+) storage proteins. Chromogranins A and B also interact with the IP(3)Rs and activate the IP(3)R/Ca(2+) channels. In experiments with both neuroendocrine PC12 and nonneuroendocrine NIH3T3 cells, in which the number of secretory granules present was changed by either suppression or induction of secretory granule formation, secretory granules were demonstrated to account for >70% of the IP(3)-induced Ca(2+) releases in the cytoplasm. Moreover, the IP(3) sensitivity of secretory granule IP(3)R/Ca(2+) channels is at least approximately 6- to 7-fold more sensitive than those of the endoplasmic reticulum, thus enabling secretory granules to release Ca(2+) ahead of the endoplasmic reticulum. Further, there is a direct correlation between the number of secretory granules and the IP(3) sensitivity of cytoplasmic IP(3)R/Ca(2+) channels and the increased ratio of IP(3)-induced cytoplasmic Ca(2+) release, highlighting the importance of secretory granules in the IP(3)-dependent Ca(2+) signaling. Given that secretory granules are present in all secretory cells, these results presage critical roles of secretory granules in the control of cytoplasmic Ca(2+) concentrations in other secretory cells.-Yoo, S. H. Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca(2+) signaling in the cytoplasm of neuroendocrine cells.