G Protein‐Coupled Receptor Kinase 4γ Interacts with Inactive Gα s and Gα 13 without Competing with Gβγ

G protein‐coupled receptors (GPCRs) are regulated by multiple families of kinases including G protein‐coupled receptor kinases (GRKs). GRK4 has been shown to be constitutively active towards GPCRs, and polymorphisms of GRK4γ are linked to, and experimentally can cause, hypertension. To better understand GRK4γ we examined the interactions between GRK4γ and Gα and Gβ subunits of heterotrimeric G proteins. Because GRK4 has been shown to inhibit Gα s ‐coupled GPCR signaling and does not contain the PH domain found in GRK2, we hypothesized that GRK4γ would interact with active Gα s , but not Gβ. We examined GRK4γ and G protein interactions through co‐immunoprecipitation of GRK4γ with inactive and active Gα proteins and Gβ. Surprisingly, GRK4γ preferentially interacts with inactive Gα s along with Gβ to a greater extent than active Gα s . GRK4γ also interacts with inactive Gα 13 along with Gβ to a lesser extent than Gα s . These results are in contrast to GRK2, which interacts with active Gα q , but not inactive Gα q . 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 the binding to inactive Gα s and Gβ may explain the constitutive activity of GRK4γ towards Gα s coupled receptors. Support provided by the American Health Assistance Foundation.