G protein-coupled receptor kinase 4gamma interacts with inactive Galpha(s) and Galpha13.

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 GRK4gamma are linked to hypertension. We examined, through co-immunoprecipitation, the interactions between GRK4gamma and the Galpha and Gbeta subunits of heterotrimeric G proteins. Because GRK4 has been shown to inhibit Galpha(s)-coupled GPCR signaling and lacks a PH domain, we hypothesized that GRK4gamma would interact with active Galpha(s), but not Gbeta. Surprisingly, GRK4gamma preferentially interacts with inactive Galpha(s) and Gbeta to a greater extent than active Galpha(s). GRK4gamma also interacts with inactive Galpha(13) and Gbeta. Functional studies demonstrate that wild-type GRK4gamma, but not kinase-dead GRK4gamma, ablates isoproterenol-mediated cAMP production indicating that the kinase domain is responsible for GPCR regulation. This evidence suggests that binding to inactive Galpha(s) and Gbeta may explain the constitutive activity of GRK4gamma towards Galpha(s)-coupled receptors.