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J. Biol. Chem., Vol. 280, Issue 36, 31708-31713, September 9, 2005

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A Role for G_z in Pancreatic Islet -Cell Biology^*

Michelle E. Kimple, Andrew B. Nixon, Patrick Kelly, Candice L. Bailey, Kenneth H. Young¶, Timothy A. Fields¶, and Patrick J. Casey||

From the Department of Pharmacology and Cancer Biology and ^¶Department of Pathology, Duke University, Medical Center, Durham, North Carolina 27710

Glucose-stimulated insulin secretion and -cell growth are important facets of pancreatic islet -cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G_z and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic -cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G_z impacts are intact in -cells, and G_z activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) -cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G_i family members are not involved in this process in this -cell line. Indeed, overexpression of a selective deactivator of G_z, the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G_z expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) -cell line couples to G_z predominantly and perhaps even exclusively. These data provide the first evidence for G_z signaling in pancreatic -cells, and identify an endogenous receptor-mediated signaling process in -cells that is dependent on G_z function.

Received for publication, June 20, 2005

^* This work was supported in part by Grant GM55717 from the National Institutes of Health (to P. J. C.), National Institutes of Health Clinical Scientist Development Award DK62833 (to T. A. F.), and National Institutes of Health training Grants DK07568 and DK067799 (to M. E. K.), and GM19663 (to A. B. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Duke University Medical School Alumni Scholarship.

^|| To whom correspondence should be addressed. Tel.: 919-613-8613; Fax: 919-613-8642; E-mail: casey006{at}mc.duke.edu.

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