Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta-cells
Ca. Aspinwall et al., Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta-cells, J BIOL CHEM, 275(29), 2000, pp. 22331-22338
The signaling pathway by which insulin stimulates insulin secretion and inc
reases in intracellular free Ca2+ concentration ([Ca2+](i)) in isolated mou
se pancreatic beta-cells and clonal beta-cells was investigated. Applicatio
n of insulin to single beta-cells resulted in increases in [Ca2+](i) that w
ere of lower magnitude, slower onset, and longer lifetime than that observe
d 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) change
s and insulin secretion at single beta-cells were abolished by treatment wi
th 100 nM wortmannin or 1 mu M thapsigargin; however, they were unaffected
by 10 mu M U73122, 20 mu M nifedipine, or removal of Ca2+ from the medium.
Insulin-stimulated insulin secretion was also abolished by treatment with 2
mu M bisin-dolylmaleimide I, but [Ca2+](i) changes were unaffected. In an
insulin receptor substrate-1 gene disrupted beta-cell tumor line, insulin d
id not evoke either [Ca2+](i) changes or insulin secretion. The data sugges
t that autocrine-activated increases in [Ca2+](i) are due to release of int
racellular Ca2+ stores, especially the endoplasmic reticulum, mediated by i
nsulin receptor substrate-1 and phosphatidylinositol 3-kinase, Autocrine ac
tivation of insulin secretion is mediated by the increase in [Ca2+](i) and
activation of protein kinase C.