LOCALIZATION OF INOSITOL TRISPHOSPHATE RECEPTOR SUBTYPE-3 TO INSULIN AND SOMATOSTATIN SECRETORY GRANULES AND REGULATION OF EXPRESSION IN ISLETS AND INSULINOMA CELLS

Calcium ions play a central role in stimulus-secretion coupling in pan creatic beta cells, and an elevation of cytosolic Ca2+ levels is neces sary for insulin secretion. Inositol 1,4,5,-trisphosphate mobilizes in tracellular Ca2+ stores in the (b)eta cell by binding to specific rece ptors that are ligand-activated Ca2+ channels. The inositol trisphosph ate receptors comprise a family of structurally related proteins with distinct but overlapping tissue distributions. Previous studies indica ted that the predominant inositol trisphosphate receptor subtype expre ssed in rat pancreatic islets was the protein designated IP3R-3. We ha ve confirmed the expression of IP3R-3 in pancreatic islets by immunohi stocytochemistry and localized this protein to the secretory granules of insulin-secreting beta cells and somatostatin-secreting delta cells by immunogold electron microscopy. Secretory granules contain high le vels of Ca2+, and the presence of IP3R-3 in the granule provides a mec hanism for mobilizing granule Ca2+ stores in response to glucose and/o r hormones. The release of Ca2+ from granule stores would increase the Ca2+ concentration in the surrounding cytoplasm and promote rapid exo cytosis of granules, especially those granules in close proximity to t he 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 insulinoma RINm5F cells cult ured in 25 mM glucose compared with cells cultured in 5 mM glucose. Th e localization of IP3R-3 to secretory granules of insulin-secreting be ta cells and somatostatin-secreting delta cells suggests that granule Ca2+ stores actively participate in the secretory process and that the ir release is regulated by inositol 1,4,5-trisphosphate. The regulatio n of IP3R-3 levels by glucose, diabetes, and refeeding may allow the b eta cell to adjust the insulin secretory response to changing physiolo gical conditions.