{"doi":"10.1016/j.jbc.2023.105293","title":"Gαs is dispensable for β-arrestin coupling but dictates GRK selectivity and is predominant for gene expression regulation by β2-adrenergic receptor","abstract":"β-arrestins play a key role in G protein–coupled receptor (GPCR) internalization, trafficking, and signaling. Whether β-arrestins act independently of G protein–mediated signaling has not been fully elucidated. Studies using genome-editing approaches revealed that whereas G proteins are essential for mitogen-activated protein kinase activation by GPCRs., β-arrestins play a more prominent role in signal compartmentalization. However, in the absence of G proteins, GPCRs may not activate β-arrestins, thereby limiting the ability to distinguish G protein from β-arrestin-mediated signaling events. We used β2-adrenergic receptor (β2AR) and its β2AR-C tail mutant expressed in human embryonic kidney 293 cells wildtype or CRISPR–Cas9 gene edited for Gα s , β-arrestin1/2, or GPCR kinases 2/3/5/6 in combination with arrestin conformational sensors to elucidate the interplay between Gα s and β-arrestins in controlling gene expression. We found that Gα s is not required for β2AR and β-arrestin conformational changes, β-arrestin recruitment, and receptor internalization, but that Gα s dictates the GPCR kinase isoforms involved in β-arrestin recruitment. By RNA-Seq analysis, we found that protein kinase A and mitogen-activated protein kinase gene signatures were activated by stimulation of β2AR in wildtype and β-arrestin1/2-KO cells but absent in Gα s -KO cells. These results were validated by re-expressing Gα s in the corresponding KO cells and silencing β-arrestins in wildtype cells. These findings were extended to cellular systems expressing endogenous levels of β2AR. Overall, our results support that Gs is essential for β2AR-promoted protein kinase A and mitogen-activated protein kinase gene expression signatures, whereas β-arrestins initiate signaling events modulating Gα s -driven nuclear transcriptional activity.","journal":"Journal of Biological Chemistry","year":2023,"id":341676,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"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":647205,"name":"Justine S. Paradis","orcid":null,"position":1,"is_corresponding":false},{"id":85449,"name":"Adam Officer","orcid":"0000-0003-2913-6051","position":2,"is_corresponding":false},{"id":1077668,"name":"Sendi Rafael Adame-Garcia","orcid":"0000-0002-5665-8333","position":3,"is_corresponding":false},{"id":488479,"name":"Xingyu Wu","orcid":"0000-0001-9289-7115","position":4,"is_corresponding":false},{"id":1076678,"name":"Edda S. F. Matthees","orcid":"0000-0002-7760-5900","position":5,"is_corresponding":false},{"id":227703,"name":"Benjamin Barsi‐Rhyne","orcid":"0000-0002-6610-1766","position":6,"is_corresponding":false},{"id":641723,"name":"Dana J. Ramms","orcid":"0000-0002-7700-1728","position":7,"is_corresponding":false},{"id":737451,"name":"Lauren Clubb","orcid":"0000-0003-1480-7043","position":8,"is_corresponding":false},{"id":646270,"name":"Monica Acosta","orcid":"0000-0003-4202-7765","position":9,"is_corresponding":false},{"id":987291,"name":"Pablo Tamayo","orcid":"0000-0002-0893-8023","position":10,"is_corresponding":false},{"id":251464,"name":"Michel Bouvier","orcid":"0000-0003-1128-0100","position":11,"is_corresponding":false},{"id":255551,"name":"Asuka Inoue","orcid":"0000-0003-0805-4049","position":12,"is_corresponding":false},{"id":320027,"name":"Mark von Zastrow","orcid":"0000-0003-1375-6926","position":13,"is_corresponding":false},{"id":578790,"name":"Carsten Hoffmann","orcid":"0000-0003-0884-9300","position":14,"is_corresponding":false},{"id":273870,"name":"J. Silvio Gutkind","orcid":"0000-0002-5150-4482","position":15,"is_corresponding":false},{"id":969718,"name":"Valeria Burghi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:11:08.077724Z","pmid":"37774973","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":[]}