title: Differential Regulation of 6- and 7-Transmembrane Helix Variants of μ-Opioid Receptor in Response to Morphine Stimulation.
abstract: The pharmacological effect of opioids originates, at the cellular level, by their interaction with the μ-opioid receptor (mOR) resulting in the regulation of voltage-gated Ca2+ channels and inwardly rectifying K+ channels that ultimately modulate the synaptic transmission. Recently, an alternative six trans-membrane helix isoform of mOR, (6TM-mOR) has been identified, but its function and signaling are still largely unknown. Here, we present the structural and functional mechanisms of 6TM-mOR signaling activity upon binding to morphine. Our data suggest that despite the similarity of binding modes of the alternative 6TM-mOR and the dominant seven trans-membrane helix variant (7TM-mOR), the interaction with morphine generates different dynamic responses in the two receptors, thus, promoting the activation of different mOR-specific signaling pathways. We characterize a series of 6TM-mOR-specific cellular responses, and observed that they are significantly different from those for 7TM-mOR. Morphine stimulation of 6TM-mOR does not promote a cellular cAMP response, while it increases the intracellular Ca2+ concentration and reduces the cellular K+ conductance. Our findings indicate that 6TM-mOR has a unique contribution to the cellular opioid responses. Therefore, it should be considered as a relevant target for the development of novel pharmacological tools and medical protocols involving the use of opioids.
authors.affiliation: Biochemistry and Biophysics Department, University of North Carolina, 120 Mason Farm Road, Chapel Hill, NC, United States of America, 27599.
authors.forename: Marino
authors.initials: M
authors.lastname: Convertino
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, 740 Dr. Penfield Avenue, Montreal, Quebec, Canada, H3A 0G1.
authors.forename: Alexander
authors.initials: A
authors.lastname: Samoshkin
authors.affiliation: Bluestone Center for Clinic Research, New York University, New York, NY, United States of America, 10010.
authors.forename: Chi T
authors.initials: CT
authors.lastname: Viet
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina, 385 S. Columbia Street, Chapel Hill, NC, United States of America, 27599.
authors.forename: Josee
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Department of Physiology and Cell Information Systems, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 0B1.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Li Fraine
authors.affiliation: Department of Physiology and Cell Information Systems, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 0B1.
authors.forename: Reza
authors.initials: R
authors.lastname: Sharif-Naeini
authors.affiliation: Bluestone Center for Clinic Research, New York University, New York, NY, United States of America, 10010.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Schmidt
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina, 385 S. Columbia Street, Chapel Hill, NC, United States of America, 27599.
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, 740 Dr. Penfield Avenue, Montreal, Quebec, Canada, H3A 0G1.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: Biochemistry and Biophysics Department, University of North Carolina, 120 Mason Farm Road, Chapel Hill, NC, United States of America, 27599.|Center for Pain Research and Innovation, University of North Carolina, 385 S. Columbia Street, Chapel Hill, NC, United States of America, 27599.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009020:Morphine / Q000494:pharmacology*; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; D009020:Morphine