Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca²⁺ signaling in the cytoplasm of neuroendocrine cells

Of all the intracellular organelles, secretory granules contain by far the highest calcium concentration; secretory granules of typical neuroendocrine chromaffin cells contain ~40 mM Ca²⁺ and occupy ~20% cell volume, accounting for >60% of total cellular calcium. They also contain the majority of cellular inositol 1,4,5-trisphosphate receptors (IP₃Rs) in addition to the presence of >2 mM of chromogranins A and B that function as high-capacity, low-affinity Ca²⁺ storage proteins. Chromogranins A and B also interact with the IP₃Rs and activate the IP₃R/Ca²⁺ 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 IP₃-induced Ca²⁺ releases in the cytoplasm. Moreover, the IP₃ sensitivity of secretory granule IP₃R/Ca²⁺ channels is at least ~6- to 7-fold more sensitive than those of the endoplasmic reticulum, thus enabling secretory granules to release Ca²⁺ ahead of the endoplasmic reticulum. Further, there is a direct correlation between the number of secretory granules and the IP₃ sensitivity of cytoplasmic IP₃R/Ca²⁺ channels and the increased ratio of IP₃-induced cytoplasmic Ca²⁺ release, highlighting the importance of secretory granules in the IP₃-dependent Ca²⁺ signaling. Given that secretory granules are present in all secretory cells, these results presage critical roles of secretory granules in the control of cytoplasmic Ca²⁺ concentrations in other secretory cells.--Yoo, S. H. Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca²⁺ signaling in the cytoplasm of neuroendocrine cells.