title: Functional characterization of human variants of the mu-opioid receptor gene.
abstract: Opioids and their receptors have an important role in analgesia and alcohol and substance use disorders (ASUD). We have identified several naturally occurring amino acid changing variants of the human mu-opioid receptor (MOR), and assessed the functional consequences of these previously undescribed variants in stably expressing cell lines. Several of these variants had altered trafficking and signaling properties. We found that an L85I variant showed significant internalization in response to morphine, in contrast to the WT MOR, which did not internalize in response to morphine. Also, when L85I and WT receptor were coexpressed, WT MOR internalized with the L85I MOR, suggesting that, in the heterozygous condition, the L85I phenotype would be dominant. This finding is potentially important, because receptor internalization has been associated with development of tolerance to opiate analgesics. In contrast, an R181C variant abolished both signaling and internalization in response to saturating doses of the hydrolysis-resistant enkephalin [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO). Coexpression of the R181C and WT receptor led to independent trafficking of the 2 receptors. S42T and C192F variants showed a rightward shift in potency of both morphine and DAMGO, whereas the S147C variant displayed a subtle leftward shift in morphine potency. These data suggest that these and other such variants may have clinical relevance to opioid responsiveness to both endogenous ligands and exogenous drugs, and could influence a broad range of phenotypes, including ASUD, pain responses, and the development of tolerance to morphine.
authors.affiliation: Ernest Gallo Clinic and Research Center, Emeryville, CA 94608, USA. ajayrav@gallo.ucsf.edu
authors.forename: Ajay
authors.initials: A
authors.lastname: Ravindranathan
authors.forename: Geoff
authors.initials: G
authors.lastname: Joslyn
authors.forename: Margaret
authors.initials: M
authors.lastname: Robertson
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schuckit
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
authors.forename: Raymond L
authors.initials: RL
authors.lastname: White
mesh_terms: D019943:Amino Acid Substitution; D000701:Analgesics, Opioid / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009020:Morphine / Q000494:pharmacology; D009154:Mutation; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014316:Tritium
chemical_list: D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D000242:Cyclic AMP