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The interaction of chemoattractant receptors andGα16 was studied to provide the molecular basis to elucidatethe interaction of chemoattractant receptors with Gα16 subunit,thereby possibly contributing to finding novel targets for designingnew type of G protein antagonists with anti-inflammatoryeffects. Experiments were performed to characterize theGα16 subunit domains responsible for efficient coupling tochemoattractant receptors. Thus, a series of chimeric Gα11/Gα16and Gα16/Gα11 cDNA constructs were expressed, and the abilityof chimeric proteins to mediate C5a, IL-8, and fMLP-inducedrelease of inositol phosphate in transfected Cos-7 cells wastested. The results showed that short stretches of residues 154 toresidue 167 and from residue 174 to residue 195 of Gα16contribute to efficient coupling to the C5a receptor. On the otherhand, a stretch of amino acid residues 220- 240 of Gα16 that isnecessary for interacting with C5a receptor did not play any rolein the interaction with IL-8 receptor. However, a stretch fromresidue 155 to residue 195 of Gα16 was found to be crucial forefficient coupling to IL-8 receptor in concert with C-terminal 30amino acid residues of this α subunit. Coupling profiles of avariety of chimeras, composed of Gα11 and Gα16, to fMLPreceptor indicate that the C-terminal 30 amino acids are mostcritical for the coupling of Gα16 to fMLP receptor. Takentogether, Gα16 subunit recruits multiple and distinctive couplingregions, depending on the type of receptors, to interact.