Functional characterization of human variants of the mu-opioid receptor gene
| Autor: | Ajay Ravindranathan, Margaret Robertson, Raymond L. White, Marc A. Schuckit, Jennifer L. Whistler, Geoff Joslyn |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Enkephalin
media_common.quotation_subject Receptors Opioid mu Pharmacology Transfection Tritium Binding Competitive Cell Line chemistry.chemical_compound Cyclic AMP medicine Humans Internalization Receptor media_common Microscopy Confocal Multidisciplinary Dose-Response Relationship Drug Morphine Chemistry Cell Membrane Genetic Variation Enkephalin Ala(2)-MePhe(4)-Gly(5) Biological Sciences Immunohistochemistry Endocytosis Analgesics Opioid DAMGO nervous system Amino Acid Substitution Opioid Mutation Signal transduction μ-opioid receptor Opiate Signal Transduction medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:10811-10816 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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