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 similar to 40 mM Ca2+ and occupy similar to 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 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 similar to 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. FASEB J. 24, 653-664 (2010). www.fasebj.org