Calcium ions play a central role in stimulussecretion coupling in pancreatic f3 cells, and an elevation of cytosolic Ca2+ levels is necessary for insulin secretion. Inositol 1,4,5-trisphosphate mobilizes intracellular Ca2+ stores in the (3 cell by binding to specific receptors that are ligand-activated Ca2+ channels. The inositol trisphosphate receptors comprise a family of structurally related proteins with distinct but overlapping tissue distributions. Previous studies indicated that the predominant inositol trisphosphate receptor subtype expressed in rat pancreatic islets was the protein designated IP3R-3. We have confirmed the expression of IP3R-3 in pancreatic islets by immunohistocytochemistry and localized this protein to the secretory granules ofinsulin-secreting (8 cells and somatostatin-secreting 8 cells by immunogold electron microscopy. Secretory granules contain high levels of Ca2+, and the presence of IP3R-3 in the granule provides a mechanism for mobilizing granule Ca2+ stores in response to glucose and/or hormones. The release of Ca2+ from granule stores would increase the Ca2+ concentration in the surrounding cytoplasm and promote rapid exocytosis ofgranules, especially those granules in close proximity to the plasma membrane. The levels of IP3R-3 were increased in pancreatic islets of diabetic rats and rats that had been refed after a period of fasting. They were also increased in rat insuloma RINmSF cells cultured in 25 mM glucose compared with cells cultured in 5 mM glucose.The localization of IP3R-3 to secretory granules of insllinsecreting (3cells and somatostatin-secreting 5cells suggests that granule Ca2+ stores actively participate in the secretory process and that their release is regulated by inositol 1,4,5-trisphosphate. The regulation of IP3R-3 levels by glucose, diabetes, and refeeding may allow the (3 cell to adjust the insulin secretory response to changing physiological conditions. An increase in intracellular Ca2+ concentration is required for insulin secretion in pancreatic p cells (1-3), and the oscillatory electrical activity and correlated pulsatile release of insulin observed in P cells in response to glucose appear to depend upon a close interplay between plasma membrane ion channels and intracellular inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ stores (4). Secretory granules contain high levels of a readily mobilizable pool of Ca2+ whose release is promoted by glucose-induced depolarization of the 3-cell plasma membrane, implying that secretory granules may actively participate in the regulation of the Ca2+ concentration in the surrounding cytoplasm (5-10). However, the mechanisms regulating the release of granular Ca2+ stores in (3 cells are unknown.IP3 plays an important role in the regulation of insulin secretion. The cellular actions of IP3 are mediated by specific receptors that function as ligand-activated, Ca2+-selective channels (11). They have been identified in the endoplasmic reticulum (12), nucleus (13) (11,20,21). IP3 receptor subtype 3 (IP3R-3) ...
