title: Functional μ-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.
abstract: The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders.
  
  
  
  The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: César
authors.initials: C
authors.lastname: Quiroz
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: William
authors.initials: W
authors.lastname: Rea
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Ning-Sheng
authors.initials: NS
authors.lastname: Cai
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Josefa
authors.identifier: 0000-0002-2479-4162
authors.initials: J
authors.lastname: Mallol
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Carme
authors.identifier: 0000-0003-2869-6882
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Enric I
authors.identifier: 0000-0003-4992-7440
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Center for Biomedical Research in Neurodegenerative Diseases Network and sferre@intra.nida.nih.gov vcasado@ub.edu.|Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona, 08028 Barcelona, Spain, and.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224 sferre@intra.nida.nih.gov vcasado@ub.edu.
authors.forename: Sergi
authors.identifier: 0000-0002-1747-1779
authors.initials: S
authors.lastname: Ferré
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein; D059290:Dopaminergic Neurons / Q000187:drug effects; D019004:Galanin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D020239:Receptor Cross-Talk; D044091:Receptor, Galanin, Type 1 / Q000235:genetics / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000235:genetics / Q000378:metabolism; D044088:Receptors, Galanin / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008024:Ligands; C485764:OPRM1 protein, human; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D044088:Receptors, Galanin; D017450:Receptors, Opioid, mu; D019004:Galanin; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases
keywords: MAPK; dopamine; galanin receptor; opioid receptor; receptor heteromer; ventral tegmental area