Preferential Gs protein coupling of the galanin Gal(1) receptor in the mu-opioid-Gal(1) receptor heterotetramer

• Type of Material: Article
• Authors: Paulo A. De Oliveira, National Institutes of Health; Estefania Moreno, University of Barcelona; Nil Casajuana-Martin, Autonomous University of Barcelona; Veronica Casado-Anguera, University of Barcelona; Ning-Sheng Cai, National Institutes of Health; Gisela Andrea Camacho-Hernandez, National Institutes of Health; Hu Zhu, National Institutes of Health; Alessandro Bonifazi, National Institutes of Health; Matthew D. Hall, National Institutes of Health; David Weinshenker, Emory University; Amy Hauck Newman, National Institutes of Health; Diomedes E. Logothetis, Northeastern University; Vicent Casado, University of Barcelona; Leigh D. Plant, Northeastern University; Leonardo Pardo, Autonomous University of Barcelona; Sergi Ferre, National Institutes of Health
• Language: English
• Date: 2022-08-01
• Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Elsevier
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.phrs.2022.106322
• Title of Journal or Parent Work: PHARMACOLOGICAL RESEARCH
• Volume: 182
• Start Page: 106322
• End Page: 106322
• Grant/Funding Information: National Institute on Drug Abuse intramural research funds (P.A.D.O., N.-S.C., G.A.C.-H., A.B., A.H.N., S.F.); National Center for Advancing Translational Sciences (NCATS) (H.Z., M.D.H.); Trans-NIH HEAL Initiative (the NIH HEAL Initiative Data policy is available at: https://heal.nih.gov/about/public-access-data”) (P.A.D.O., H.Z., M.D.H.); ‘Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación’ (MCIN/AEI) and FEDER grant SAF2017-87629-R (E.M., V.C.-A., V.C.); MCIN/AEI grants 10.13039/501100011033 (Juan de la Cierva fellowship; FJC2019-04102-I; V.C.-A.) and PID2020-113938RB-I00 (E.M, V.C.-A, V.C.); “Generalitat de Catalunya” grant 2017-SGR-1497 (E.M., V.C.-A., V.C.); MCIN/AEI grant PID2019-109240RB-I00 (NCM, LP); National Institutes of Health grant R01DA049257 (D.W.); National Institutes of Health grant R01HL144615 (L.D.P.).
• Keywords: HETEROMERS; ANTAGONISTS; Total internal reflection fluorescence microscopy; CRYSTAL-STRUCTURE; ALLOSTERIC INTERACTIONS; OLIGOMERIZATION; FUNCTIONAL SELECTIVITY; Life Sciences & Biomedicine; CHANNELS; INTERNALIZATION; G protein coupled receptor oligomerization; Science & Technology; Galanin receptors; STOICHIOMETRY; Opioid receptors; Pharmacology & Pharmacy; HOMODIMERIZATION
• Research Categories: Health Sciences, Pharmacology; Biology, Molecular

Abstract

Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance.