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J. Biol. Chem., Vol. 276, Issue 26, 23667-23673, June 29, 2001
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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
A New Pathway for Glucose-dependent Insulinotropic
Polypeptide (GIP) Receptor Signaling
EVIDENCE FOR THE INVOLVEMENT OF PHOSPHOLIPASE
A2 IN GIP-STIMULATED INSULIN SECRETION*
,
-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.
*
This work was supported by Canadian Medical Research Council
Grant 590007 and by funds from the Canadian Diabetes Association.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Medical Research Council doctoral research fellowship.
§
To whom correspondence should be addressed: Dept. of Physiology,
Faculty of Medicine, University of British Columbia, 2146 Health
Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Tel.:
604-822-3088; Fax: 604-822-6048; E-mail:
mcintoch@interchange.ubc.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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