{"doi":"10.3390/biom13101552","title":"G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D2 Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation","abstract":"The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R-β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R-β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation.","journal":"Biomolecules","year":2023,"id":343460,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":354433,"name":"Noelia Boldizsar","orcid":"0000-0003-0299-4697","position":1,"is_corresponding":false},{"id":1081464,"name":"Kayla A. Schardien","orcid":null,"position":2,"is_corresponding":false},{"id":1081008,"name":"Nora S. Madaras","orcid":"0000-0003-2166-8336","position":3,"is_corresponding":false},{"id":356253,"name":"Blair K. A. Willette","orcid":"0000-0002-8763-1096","position":4,"is_corresponding":false},{"id":1081465,"name":"Laura R. Inbody","orcid":null,"position":5,"is_corresponding":false},{"id":1081466,"name":"Christopher Dasaro","orcid":null,"position":6,"is_corresponding":false},{"id":357519,"name":"Amy E. Moritz","orcid":null,"position":7,"is_corresponding":false},{"id":1047653,"name":"Julia Drube","orcid":"0000-0001-6188-2279","position":8,"is_corresponding":false},{"id":1076676,"name":"Raphael S. Haider","orcid":"0000-0002-5924-6545","position":9,"is_corresponding":false},{"id":356256,"name":"R. Benjamin Free","orcid":"0000-0002-2428-0487","position":10,"is_corresponding":false},{"id":1081467,"name":"Carsten Hoffman","orcid":null,"position":11,"is_corresponding":false},{"id":356257,"name":"David R. Sibley","orcid":"0000-0002-0624-962X","position":12,"is_corresponding":false},{"id":290977,"name":"Marta Sánchez‐Soto","orcid":"0000-0003-3343-5628","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:11:21.758449Z","pmid":"37892234","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}