Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family.

The vasopressin receptor family is unique among all classes of peptide receptors in that its individual members couple to different subsets of G proteins. The V1a vasopressin receptor, for example, is preferentially linked to G proteins of the Gq/11 class (biochemical response: stimulation of phosphatidylinositol hydrolysis), whereas the V2 vasopressin receptor is selectively coupled to Gs (biochemical response: stimulation of adenylyl cyclase). To elucidate the structural basis underlying this functional heterogeneity, we have systematically exchanged different intracellular domains between the V1a and V2 receptors. Transient expression of the resulting hybrid receptors in COS-7 cells showed that all mutant receptors containing V1a receptor sequence in the second intracellular loop were able to activate the phosphatidylinositol pathway with high efficiency. On the other hand, only those hybrid receptors containing V2 receptor sequence in the third intracellular loop were capable of efficiently stimulating cAMP production. These findings suggest that the differential G protein coupling profiles of individual members of a structurally closely related receptor subfamily can be determined by different single intracellular receptor domains.