期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 43, 页码 29489-29498出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.038034
关键词
-
资金
- National Institutes of Health [K01DK078625, R01DK075772]
- W. M. Keck Foundation
Membrane cholesterol modulates the ability of glucose to stimulate insulin secretion from pancreatic beta-cells. The molecular mechanism by which this occurs is not understood. Here, we show that in cultured beta-cells, cholesterol acts through phosphatidylinositol 4,5-bisphosphate (PIP(2)) to regulate actin dynamics, plasma membrane potential, and glucose-stimulated insulin secretion. Cholesterol-overloaded beta-cells exhibited decreased PIP(2) hydrolysis, with diminished glucose-induced actin reorganization, membrane depolarization, and insulin secretion. The converse findings were observed in cholesterol-depleted cells. These results support a model in which cholesterol depletion is coupled through PIP(2) to enhance both plasma membrane Ca(2+) influx from the extracellular space, as well as inositol 1,4,5-triphosphate-stimulated Ca(2+) efflux from intracellular stores. The inability to increase cytosolic Ca(2+) may be the main underlying factor to account for impaired glucose-stimulated insulin secretion in cholesterol-overloaded beta-cells.
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