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J. Biol. Chem., Vol. 282, Issue 13, 9547-9555, March 30, 2007

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Inhibition of G_i2 Activation by G_i3 in CXCR3-mediated Signaling^*

Brian D. Thompson¹, Yongzhu Jin, Kevin H. Wu, Richard A. Colvin, Andrew D. Luster, Lutz Birnbaumer^¶, and Mei X. Wu²

From the Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, ^¶NIEHS, Transmembrane Signaling Group, Laboratory of Signal Transduction, National Institutes of Health, Research Triangle Park, North Carolina 27709, and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

G protein-coupled receptors (GPCRs) convey extracellular stimulation into dynamic intracellular action, leading to the regulation of cell migration and differentiation. T lymphocytes express G_i2 and G_i3, two members of the G_i/o protein family, but whether these two G_i proteins have distinguishable roles guiding T cell migration remains largely unknown because of a lack of member-specific inhibitors. This study details distinct G_i2 and G_i3 effects on chemokine receptor CXCR3-mediated signaling. Our data showed that G_i2 was indispensable for T cell responses to three CXCR3 ligands, CXCL9, CXCL10, and CXCL11, as the lack of G_i2 abolished CXCR3-stimulated migration and guanosine 5'-3-O-(thio)triphosphate (GTPS) incorporation. In sharp contrast, T cells isolated from G_i3 knock-out mice displayed a significant increase in both GTPS incorporation and migration as compared with wild type T cells when stimulated with CXCR3 agonists. The increased GTPS incorporation was blocked by G_i3 protein in a dose-dependent manner. G_i3-mediated blockade of G_i2 activation did not result from G_i3 activation, but instead resulted from competition or steric hindrance of G_i2 interaction with the CXCR3 receptor via the N terminus of the second intracellular loop. A mutation in this domain abrogated not only G_i2 activation induced by a CXCR3 agonist but also the interaction of G_i3 to the CXCR3 receptor. These findings reveal for the first time an interplay of G_i proteins in transmitting G protein-coupled receptor signals. This interplay has heretofore been masked by the use of pertussis toxin, a broad inhibitor of the G_i/o protein family.

Received for publication, November 27, 2006 , and in revised form, January 16, 2007.

^* This work was supported in part by National Institutes of Health Grants AI050822 and AI070785, Research Scholar Grant RSG-01-178-01-MGO from the American Cancer Society, Senior Research Award 1657 from the Crohn & Colitis Foundation of America, and by the Intramural Research Program of the NIEHS, National Institutes of Health (to L. B.), and National Institutes of Health Grant DK074449 (to A. D. L.). 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.

¹ Supported in part by National Institutes of Health Training Grant T32 AR07098-31 from the Department of Dermatology, Harvard Medical School.

² To whom correspondence should be addressed: Wellman Center of Photomedicine, Massachusetts General Hospital, 55 Fruit St., Edwards 222, Boston, MA 02114. Tel.: 617-726-1298; Fax: 617-726-1208; E-mail: mwu2{at}partners.org.

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