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J. Biol. Chem., Vol. 276, Issue 26, 23667-23673, June 29, 2001

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A New Pathway for Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Signaling
EVIDENCE FOR THE INVOLVEMENT OF PHOSPHOLIPASE A₂ IN GIP-STIMULATED INSULIN SECRETION^*

Jan A. Ehses, Shelter S. T. Lee, Raymond A. Pederson, and Christopher H. S. McIntosh^§

From the Department of Physiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

The hormone glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of insulin secretion. GIP has been shown to increase adenylyl cyclase activity, elevate intracellular Ca²⁺ levels, and stimulate a mitogen-activated protein kinase pathway in the pancreatic -cell. In the current study we demonstrate a role for arachidonic acid in GIP-mediated signal transduction. Static incubations revealed that both GIP (100 nM) and ATP (5 µM) significantly increased [³H]arachidonic acid ([³H]AA) efflux from transfected Chinese hamster ovary K1 cells expressing the GIP receptor (basal, 128 ± 11 cpm/well; GIP, 212 ± 32 cpm/well; ATP, 263 ± 35 cpm/well; n = 4; p < 0.05). In addition, GIP receptors were shown for the first time to be capable of functionally coupling to AA production through G dimers in Chinese hamster ovary K1 cells. In a -cell model (TC-3), GIP was found to elicit [³H]AA release, independent of glucose, in a concentration-dependent manner (EC₅₀ value of 1.4 ± 0.62 nM; n = 3). Although GIP did not potentiate insulin release under extracellular Ca²⁺-free conditions, it was still capable of elevating intracellular cAMP and stimulating [³H]AA release. Our data suggest that cAMP is the proximal signaling intermediate responsible for GIP-stimulated AA release. Finally, stimulation of GIP-mediated AA production was shown to be mediated via a Ca²⁺-independent phospholipase A₂. Arachidonic acid is therefore a new component of GIP-mediated signal transduction in the -cell.

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