SCIENCE@home

Insulin Receptor Substrate 1-induced Inhibition of Endoplasmic Reticulum Ca2+ Uptake in β-Cells

Gang G. Xu,Zhiyong Gao,P. D. Borge,B. Wolf

Published 1999 in Journal of Biological Chemistry

ABSTRACT

To understand the role of the insulin receptor pathway in β-cell function, we have generated stable β-cells (βIRS1-A) that overexpress by 2-fold the insulin receptor substrate-1 (IRS-1) and compared them to vector-expressing controls. IRS-1 overexpression dramatically increased basal cytosolic Ca2+ levels from 81 to 278 nm, but it did not affect Ca2+ response to glucose. Overexpression of the insulin receptor also caused an increase in cytosolic Ca2+. Increased cytosolic Ca2+ was due to inhibition of Ca2+ uptake by the endoplasmic reticulum, because endoplasmic reticulum Ca2+ uptake and content were reduced in βIRS1-A cells. Fractional insulin secretion was significantly increased 2-fold, and there was a decrease in βIRS1-A insulin content and insulin biosynthesis. Steady-state insulin mRNA levels and glucose-stimulated ATP were unchanged. High IRS-1 levels also reduced β-cell proliferation. These data demonstrate a direct link between the insulin receptor signaling pathway and the Ca2+-dependent pathways regulating insulin secretion of β-cells. We postulate that during regulated insulin secretion, released insulin binds the β-cell insulin receptor and activates IRS-1, thus further increasing cytosolic Ca2+ by reducing Ca2+ uptake. We suggest the existence of a novel pathway of autocrine regulation of intracellular Ca2+homeostasis and insulin secretion in the β-cell of the endocrine pancreas.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-48 of 48 references · Page 1 of 1

CITED BY

Showing 1-63 of 63 citing papers · Page 1 of 1