{"doi":"10.1016/j.phrs.2025.107904","title":"Distinctive biochemical properties of the μ-opioid receptor-corticotropin- releasing factor CRF1 receptor heterotetramer","abstract":"Heteromerization of Gs with Gi protein-coupled receptors has been suggested to be necessary to sustain the canonical Gi-Gs antagonistic interaction at adenylyl cyclase (AC). These heteromers have a tetrameric quaternary structure, composed by two homodimers each one coupled to its corresponding G protein. We describe the heterotetramer formed by the Gi-coupled μ-opioid receptor (MOR) and the Gs-coupled corticotropin releasing factor CRF 1 receptor (CRF 1 R), which also sustains a canonical interaction at AC and reciprocal allosteric interactions between MOR and CRF 1 R ligands. In addition, we found that CRF 1 R can also couple to Gq proteins in the MOR-CRF 1 R heteromer, providing the frame for also canonical Gi-Gq antagonistic interactions that include other effectors, such as phospholipase C and its Ca 2 + -dependent signaling, and which control glutamate release in the central amygdala (CeA). The specific pharmacodynamic properties of the MOR-CRF 1 R heteromer, including its sensitivity to S-methadone, as well as its localization in the CeA suggest it might represent a significant pharmacological target for the analgesic, antistressor and antidepressant effects of opioids and the hyperalgesia of opioid withdrawal. • μ-opioid receptor (MOR) and CRF 1 receptor (CRF 1 R) form heterotetramers. • In the MOR-CRF 1 R heterotetramer, MOR couples to Gi and CRF 1 R couples to Gs or Gq. • Gi-Gq-MOR-CRF 1 R heterotetramers control glutamate release in the central amygdala. • S-methadone does not lose its efficacy in the MOR-CRF 1 R heterotetramer. • MOR-CRF 1 R can be target for the antistressor and antidepressant effects of opioids.","journal":"Pharmacological Research","year":2025,"id":524112,"datarank":0.253866626136687,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.012450939271571908,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.012450939271571908,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290972,"name":"Estefanía Moreno","orcid":"0000-0002-2491-5753","position":1,"is_corresponding":false},{"id":1258609,"name":"Marc Ciruela-Jardí","orcid":"0009-0001-9920-8789","position":2,"is_corresponding":false},{"id":884388,"name":"Nil Casajuana-Martín","orcid":"0000-0002-9007-274X","position":3,"is_corresponding":false},{"id":1062888,"name":"Anne K. Yauch","orcid":"0009-0000-1955-3658","position":4,"is_corresponding":false},{"id":290973,"name":"Ning-Sheng Cai","orcid":"0000-0002-7749-5131","position":5,"is_corresponding":false},{"id":335480,"name":"César Quiroz","orcid":null,"position":6,"is_corresponding":false},{"id":1396991,"name":"Ying‐Ju Chang","orcid":"0000-0002-3839-9964","position":7,"is_corresponding":false},{"id":290983,"name":"Vicent Casadó","orcid":"0000-0002-1764-3825","position":8,"is_corresponding":false},{"id":270720,"name":"Leonardo Pardo","orcid":"0000-0003-1778-7420","position":9,"is_corresponding":false},{"id":325170,"name":"Leigh D. Plant","orcid":"0000-0002-1622-1655","position":10,"is_corresponding":false},{"id":290984,"name":"Sergi Ferré","orcid":"0000-0002-1747-1779","position":11,"is_corresponding":false},{"id":1142205,"name":"William N. Sanchez","orcid":"0000-0001-7723-0064","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:07.396155Z","pmid":"40784438","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":[]}