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Antagonism between Gαi2 and Gαi3 in CXCR3‐mediated signaling

G protein‐coupled receptors (GPCR) convey extra cellular stimulation into dynamic intracellular action, regulating cell migration and differentiation. T lymphocytes express Gαi2 and Gαi3 of the Gαi protein family, but their individual roles in guidance of T cell migration have not been delineated due to a lack of member‐specific inhibitors. This study details distinct effects of Gαi2 and Gαi3 on chemokine receptor CXCR3‐mediated signaling. Gαi2 is indispensable for T cells responding to all three CXCR3 ligands CXCL9, CXCL10, and CXCL11, with the lack of Gαi2 abolishing CXCR3‐stimulated migration and GTPγS incorporation. In sharp contrast, Gαi3 specifically antagonizes Gαi2's function. Activated T cells prepared from Gαi3 knockout mice showed a significant increase in CXCR3's function by stimulating both GTPγS incorporation and migration as compared to wild type (WT) T cells. Increases in Gαi2‐mediated GTPγS incorporation could be reduced to WT levels by the addition of Gαi3 protein in a dose‐dependent manner. The Gαi3 ‐mediated blockade of Gαi2 activation did not result from Gαi3 activation, but instead, potentially resulted from competitively binding to the same domain of the CXCR3 receptor. Mutagenesis analysis demonstrates that the two Gαi proteins bind the C‐terminus of the third transmembrane domain, a mutation that abrogates not only CXCR3‐mediated migration of T cells but also binding of Gαi3 to CXCR3 receptor. These findings reveal a complexity of Gαi proteins in regulating chemokine receptor signals. The complexity has heretofore been masked by the use of pertussis toxin, an inhibitor of the enzymatic activity of the entire Gαi family.