Many different G protein-linked receptors are preferentially coupled to G proteins of the Gq/11 family. To elucidate the molecular basis underlying this selectivity, different Gq/11-coupled receptors (m3 muscarinic, V1a vasopressin, and gastrin-releasing peptide receptor) were coexpressed (in COS-7 cells) with mutant alphas subunits in which residues present at the C terminus of alphas were replaced with the corresponding alphaq/11 residues. Remarkably, whereas none of the receptors was able to interact with wild type alphas to a significant extent, all three receptors gained the ability to productively couple to a mutant alphas subunit containing a single Glu --> Asn point mutation at position -3. Moreover, the m3 muscarinic and the V1a vasopressin receptors but not the GRP receptor also gained the ability to interact with a mutant alphas subunit containing a single Gln --> Glu point mutation at position -5, indicating that the alphaq/11 residues present in these mutant G protein constructs play key roles in determining the selectivity of receptor recognition. To identify the site(s) on Gq/11-coupled receptors that can functionally interact with the C terminus of alphaq/11 subunits, we next analyzed the ability of a series of hybrid m2/m3 muscarinic receptors to interact with a mutant alphas subunit (sq5) in which the last five amino acids of alphas were replaced with the corresponding alphaq/11 sequence. Similar to the wild type m2 and m3 muscarinic receptors, none of the investigated hybrid receptors was able to efficiently interact with wild type alphas. Interestingly, however, three mutant m2 receptors in which different segments of the second and third intracellular loops were replaced with the corresponding m3 receptor sequences were identified, which, in contrast to the Gi/o-coupled wild type m2 receptor, gained the ability to efficiently activate the sq5 subunit. This observation suggests that multiple intracellular receptor domains form a binding pocket for the C terminus of G protein alphaq/11 subunits.