Localization of inositol trisphosphate receptor subtype 3 to insulin and somatostatin secretory granules and regulation of expression in islets and insulinoma cells

Olivier Blondel, Maya M. Moody, Alex M. Depaoli, Alan H. Sharp, Christopher A. Ross, Hewson Swift, Graeme I. Bell

Research output: Contribution to journalArticle

Abstract

Calcium ions play a central role in stimulus-secretion coupling in pancreatic β cells, and an elevation of cytosolic Ca2+ levels is necessary for insulin secretion. Inositol 1,4,5-trisphosphate mobilizes intracellular Ca2+ stores in the β 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 of insulin-secreting β cells and somatostatin-secreting δ 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 of granules, 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 insulinoma RINm5F cells cultured in 25 mM glucose compared with cells cultured in 5 mM glucose. The localization of IP3R-3 to secretory granules of insulin-secreting β cells and somatostatin-secreting δ cells 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 β cell to adjust the insulin secretory response to changing physiological conditions.

Original languageEnglish (US)
Pages (from-to)7777-7781
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number16
DOIs
StatePublished - Aug 2 1994

    Fingerprint

Keywords

  • calcium channel
  • diabetes mellitus
  • glucose
  • insulin secretion
  • membrane protein

ASJC Scopus subject areas

  • General

Cite this