G protein-coupled receptor kinase 4γ interacts with inactive Gαs and Gα13

G protein-coupled receptors (GPCRs) are regulated by multiple families of kinases including GPCR kinases (GRKs). GRK4 is constitutively active towards GPCRs, and polymorphisms of GRK4γ are linked to hypertension. We examined, through co-immunoprecipitation, the interactions between GRK4γ and the Gα and Gβ subunits of heterotrimeric G proteins. Because GRK4 has been shown to inhibit Gαs-coupled GPCR signaling and lacks a PH domain, we hypothesized that GRK4γ would interact with active Gαs, but not Gβ. Surprisingly, GRK4γ preferentially interacts with inactive Gαs and Gβ to a greater extent than active Gαs. GRK4γ also interacts with inactive Gα13 and Gβ. Functional studies demonstrate that wild-type GRK4γ, but not kinase-dead GRK4γ, ablates isoproterenol-mediated cAMP production indicating that the kinase domain is responsible for GPCR regulation. This evidence suggests that binding to inactive Gαs and Gβ may explain the constitutive activity of GRK4γ towards Gαs-coupled receptors.