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

Hot Off the Press – July 8, 2022

The graphical abstract of this article

The graphical abstract of this article

Published in Pharmacological Research by Paulo De Oliveira, Ph.D. and  Sergi Ferré, M.D., Ph.D. of the NIDA-IRP Integrative Neurobiology Section.

Summary

We recently demonstrated that complexes (heteromers) of μ-opioid receptors (MORs) and receptors for the neuropeptide galanin of the Gal1subtype (Gal1Rs) localized in the brainstem (in the ventral tegmental area) constitute a main population of MORs that mediate the dopaminergic effects of opioids (dopamine release and euphoric effects). In the present study, using  several in vitro and in silico biophysical, biochemical and computational techniques, we determine the preferred quaternary structure of MORs and Gal1Rs when expressed alone and when forming heteromers. When expressed alone, MORs and Gal1Rs are dimers coupled to one inhibitory Gi protein and to one stimulatory Gs protein, respectively. When co-expressed, they form heterotetramers with a MOR dimer coupled to Gi and, unexpectedly, a Gal1R dimer coupled to Gs. The study describes, for the first time, the mechanism of this heteromerization-dependent switch in G protein coupling, which is related to a change in the dimeric interface of the Gal1R in the MOR-Gal1R heteromer, and which converts galanin into an excitatory neurotransmitter that promotes cAMP accumulation.

Publication Information

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

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

In: Pharmacol Res, vol. 182, pp. 106322, 2022, ISSN: 1096-1186.

Abstract | Links

@article{pmid35750299,
title = {Preferential Gs protein coupling of the galanin Gal_{1} receptor in the µ-opioid-Gal_{1} receptor heterotetramer},
author = {Paulo A De Oliveira and Estefanía Moreno and Nil Casajuana-Martin and Verònica Casadó-Anguera and Ning-Sheng Cai and Gisela Andrea Camacho-Hernandez and Hu Zhu and Alessandro Bonifazi and Matthew D Hall and David Weinshenker and Amy Hauck Newman and Diomedes E Logothetis and Vicent Casadó and Leigh D Plant and Leonardo Pardo and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/35750299/},
doi = {10.1016/j.phrs.2022.106322},
issn = {1096-1186},
year = {2022},
date = {2022-06-01},
urldate = {2022-06-01},
journal = {Pharmacol Res},
volume = {182},
pages = {106322},
abstract = {Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal receptors (GalRs) 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 GalR when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the GalR homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-GalR heterotetramer, which is thus bound to Gs via the GalR 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 = {},
pubstate = {published},
tppubtype = {article}
}

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Recent studies have proposed that heteromers of µ-opioid receptors (MORs) and galanin Gal receptors (GalRs) 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 GalR when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the GalR homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-GalR heterotetramer, which is thus bound to Gs via the GalR 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.

Close

  • https://pubmed.ncbi.nlm.nih.gov/35750299/
  • doi:10.1016/j.phrs.2022.106322

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