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 V vasopressin receptor, for example, is preferentially linked to G proteins of the G class (biochemical response: stimulation of phosphatidylinositol hydrolysis), whereas the V vasopressin receptor is selectively coupled to G (biochemical response: stimulation of adenylyl cyclase). To elucidate the structural basis underlying this functional heterogeneity, we have systematically exchanged different intracellular domains between the V and V receptors. Transient expression of the resulting hybrid receptors in COS-7 cells showed that all mutant receptors containing V 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 V 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. 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 V vasopressin receptor, for example, is preferentially linked to G proteins of the G class (biochemical response: stimulation of phosphatidylinositol hydrolysis), whereas the V vasopressin receptor is selectively coupled to G (biochemical response: stimulation of adenylyl cyclase). To elucidate the structural basis underlying this functional heterogeneity, we have systematically exchanged different intracellular domains between the V and V receptors. Transient expression of the resulting hybrid receptors in COS-7 cells showed that all mutant receptors containing V 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 V 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.