Preferential Gs protein coupling of the galanin Gal1 receptor in the µ-opioid-Gal1 receptor heterotetramer

Paulo A De Oliveira; Estefanía Moreno; Nil Casajuana-Martin; Verònica Casadó-Anguera; Ning-Sheng Cai; Gisela Andrea Camacho-Hernandez; Hu Zhu; Alessandro Bonifazi; Matthew D Hall; David Weinshenker; Amy Hauck Newman; Diomedes E Logothetis; Vicent Casadó; Leigh D Plant; Leonardo Pardo; Sergi Ferré

doi:10.1016/j.phrs.2022.106322

Preferential Gs protein coupling of the galanin Gal₁ receptor in the µ-opioid-Gal₁ receptor heterotetramer

Pharmacol Res. 2022 Aug:182:106322. doi: 10.1016/j.phrs.2022.106322. Epub 2022 Jun 22.

Authors

Paulo A De Oliveira¹, Estefanía Moreno², Nil Casajuana-Martin³, Verònica Casadó-Anguera², Ning-Sheng Cai¹, Gisela Andrea Camacho-Hernandez⁴, Hu Zhu⁵, Alessandro Bonifazi⁴, Matthew D Hall⁵, David Weinshenker⁶, Amy Hauck Newman⁴, Diomedes E Logothetis⁷, Vicent Casadó⁸, Leigh D Plant⁹, Leonardo Pardo¹⁰, Sergi Ferré¹¹

Affiliations

¹ Integrative Neurobiology Section, USA.
² Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain.
³ Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain.
⁴ Medicinal Chemistry Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
⁵ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
⁶ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Departments of Pharmaceutical Sciences, Chemistry and Chemical Biology and Center for Drug Discovery, School of Pharmacy at the Bouvé College of Health Sciences and College of Science, Northeastern University, Boston, MA, USA.
⁸ Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institute of Biomedicine, University of Barcelona, Barcelona, Spain. Electronic address: vcasado@ub.edu.
⁹ Departments of Pharmaceutical Sciences, Chemistry and Chemical Biology and Center for Drug Discovery, School of Pharmacy at the Bouvé College of Health Sciences and College of Science, Northeastern University, Boston, MA, USA. Electronic address: l.plant@northeastern.edu.
¹⁰ Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Bellaterra, Spain. Electronic address: Leonardo.Pardo@uab.cat.
¹¹ Integrative Neurobiology Section, USA. Electronic address: sferre@intra.nida.nih.gov.

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.

Keywords: DAMGO (PubChem CID: 5462471); Endomorphin-1 (PubChem CID: 5311080); Fentanyl (PubChem CID: 3345); G protein coupled receptor oligomerization; Galanin (PubChem CID: 16133823); Galanin receptors; M40 (PubChem CID: 16133821); M617 (PubChem CID: 16158157); Methadone (PubChem CID: 4095); Naloxone (PubChem CID: 5284596); Opioid receptors; Total internal reflection fluorescence microscopy.

Published by Elsevier Ltd.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid* / pharmacology
Galanin*
Mesencephalon
Peptides
Receptors, Opioid

Substances

Analgesics, Opioid
Peptides
Receptors, Opioid
Galanin

Abstract

Publication types

MeSH terms

Substances

Grants and funding