{"doi":"10.1091/mbc.e20-06-0394","title":"The IgG3 subclass of β1-adrenergic receptor autoantibodies is an endogenous biaser of β1AR signaling","abstract":"Dysregulation of immune responses has been linked to the generation of immunoglobulin G (IgG) autoantibodies that target human β1ARs and contribute to deleterious cardiac outcomes. Given the benefits of β-blockers observed in patients harboring the IgG3 subclass of autoantibodies, we investigated the role of these autoantibodies in human β1AR function. Serum and purified IgG3(+) autoantibodies from patients with onset of cardiomyopathy were tested using human embryonic kidney (HEK) 293 cells expressing human β1ARs. Unexpectedly, pretreatment of cells with IgG3(+) serum or purified IgG3(+) autoantibodies impaired dobutamine-mediated adenylate cyclase (AC) activity and cyclic adenosine monophosphate (cAMP) generation while enhancing biased β-arrestin recruitment and Extracellular Regulated Kinase (ERK) activation. In contrast, the β-blocker metoprolol increased AC activity and cAMP in the presence of IgG3(+) serum or IgG3(+) autoantibodies. Because IgG3(+) autoantibodies are specific to human β1ARs, non-failing human hearts were used as an endogenous system to determine their ability to bias β1AR signaling. Consistently, metoprolol increased AC activity, reflecting the ability of the IgG3(+) autoantibodies to bias β-blocker toward G-protein coupling. Importantly, IgG3(+) autoantibodies are specific toward β1AR as they did not alter β2AR signaling. Thus, IgG3(+) autoantibody biases β-blocker toward G-protein coupling while impairing agonist-mediated G-protein activation but promoting G-protein-independent ERK activation. This phenomenon may underlie the beneficial outcomes observed in patients harboring IgG3(+) β1AR autoantibodies.","journal":"Molecular Biology of the Cell","year":2021,"id":200862,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":584381,"name":"Yuji Nagatomo","orcid":"0000-0002-3430-4614","position":1,"is_corresponding":false},{"id":108882,"name":"Prasenjit Prasad Saha","orcid":"0000-0003-4679-2368","position":2,"is_corresponding":false},{"id":524150,"name":"Sromona Mukherjee","orcid":"0000-0003-1958-0220","position":3,"is_corresponding":false},{"id":584382,"name":"Timothy Engelman","orcid":"0000-0002-1682-9425","position":4,"is_corresponding":false},{"id":584998,"name":"Rommel Morales","orcid":null,"position":5,"is_corresponding":false},{"id":108895,"name":"Stanley L. Hazen","orcid":"0000-0001-7124-6639","position":6,"is_corresponding":false},{"id":30816,"name":"W. H. Wilson Tang","orcid":"0000-0002-8335-735X","position":7,"is_corresponding":false},{"id":108893,"name":"Sathyamangla V Naga Prasad","orcid":"0000-0003-3984-3788","position":8,"is_corresponding":false},{"id":108888,"name":"Maradumane L. Mohan","orcid":"0000-0003-4224-150X","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:50:52.535403Z","pmid":"33534612","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":[]}