title: Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling.
abstract: The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Anesthesia, McGill University, Montreal, QC, H4A 3J1, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Samoshkin
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Marino
authors.initials: M
authors.lastname: Convertino
authors.affiliation: Bluestone Center for Clinical Research, New York University, New York, NY, 10010, USA.
authors.forename: Chi T
authors.initials: CT
authors.lastname: Viet
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wieskopf
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Oleg
authors.initials: O
authors.lastname: Kambur
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Marcovitz
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
authors.forename: Pinkal
authors.initials: P
authors.lastname: Patel
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, H3A 1G1, Canada.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Kalso
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Psychology, McGill University, Montreal, QC, H3A 1B1, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Bluestone Center for Clinical Research, New York University, New York, NY, 10010, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Schmidt
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA.|Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, H3A 0G1, Canada.|Department of Anesthesia, McGill University, Montreal, QC, H4A 3J1, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, H3A 1G1, Canada.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005724:Ganglia / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D017450:Receptors, Opioid, mu; D002118:Calcium