The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation

The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and beta-arrestins (beta arrs). Selectively engaging either the G protein or beta arr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to beta arr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates beta arr recruitment, bridge these pathways. Therefore, beta arr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand howGRK2action at theD2Rwould be disrupted whenGprotein activation is eliminated and the effect of this on beta arr recruitment. Weused two recently developed biased D2R mutants that can preferentially interact either withGproteins or beta arrs as well as a beta arr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the beta arr-preferring D2R achieves beta arr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the beta arr-preferring D2R and also contributes to beta arr recruitment at the WT D2R. Additionally, we found an additive interaction between the beta arr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving beta arr-biased signaling.