Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in β-cells

Craig A. Aspinwall, Wei Jun Qian, Michael G. Roper, Rohit N. Kulkarni, C. Ronald Kahn, Robert T. Kennedy

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

The signaling pathway by which insulin stimulates insulin secretion and increases in intracellular free Ca2+ concentration ([Ca2+](i)) in isolated mouse pancreatic β-cells and clonal β-cells was investigated. Application of insulin to single β-cells resulted in increases in [Ca2+](i) that were of lower magnitude, slower onset, and longer lifetime than that observed with stimulation with tolbutamide. Furthermore, the increases in [Ca2+](i) originated from interior regions of the cell rather than from the plasma membrane as with depolarizing stimuli. The insulin-induced [Ca2+](i) changes and insulin secretion at single β-cells were abolished by treatment with 100 nM wortmannin or 1 μM thapsigargin; however, they were unaffected by 10 μM U73122, 20 μM nifedipine, or removal of Ca2+ from the medium. Insulin-stimulated insulin secretion was also abolished by treatment with 2 μM bisindolylmaleimide I, but [Ca2+](i) changes were unaffected. In an insulin receptor substrate-1 gene disrupted β-cell tumor line, insulin did not evoke either [Ca2+](i) changes or insulin secretion. The data suggest that autocrine-activated increases in [Ca2+](i) are due to release of intracellular Ca2+ stores, especially the endoplasmic reticulum, mediated by insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Autocrine activation of insulin secretion is mediated by the increase in [Ca2+](i) and activation of protein kinase C.

Original languageEnglish (US)
Pages (from-to)22331-22338
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number29
DOIs
StatePublished - Jul 21 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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