The interaction of chemoattractant receptors and $G{alpha}_{16}$ was studied to provide the molecular basis to elucidate the interaction of chemoattractant receptors with $G{alpha}_{16}$ subunit, thereby possibly contributing to finding novel targets for designing new type of G protein antagonists with anti-inflammatory effects. Experiments were performed to characterize the $G{alpha}_{16}$ subunit domains responsible for efficient coupling to chemoattractant receptors. Thus, a series of chimeric $G{alpha}_{11}G{alpha}_{16}$ and $G{alpha}_{16}G{alpha}_{11}$ cDNA constructs were expressed, and the ability of chimeric proteins to mediate C5a, IL-8, and fMLP-induced release of inositol phosphate in transfected Cos-7 cells was tested. The results showed that short stretches of residues 154 to residue 167 and from residue 174 to residue 195 of $G{alpha}_{16}$ contribute to efficient coupling to the C5a receptor. On the other hand, a stretch of amino acid residues 220-240 of $G{alpha}_{16}$ that is necessary for interacting with C5a receptor did not play any role in the interaction with IL-8 receptor. However, a stretch from residue 155 to residue 195 of $G{alpha}_{16}$ was found to be crucial for efficient coupling to IL-8 receptor in concert with C-terminal 30 amino acid residues of this ${alpha}$ subunit. Coupling profiles of a variety of chimeras, composed of $G{alpha}_{11}G{alpha}_{16}$ to fMLP receptor indicate that the C-terminal 30 amino acids are most critical for the coupling of $G{alpha}_{16}$ to fMLP receptor. Taken together, $G{alpha}_{16}$ subunit recruits multiple and distinctive coupling regions, depending on the type of receptors, to interact.