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The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor
Abstract
The most common single nucleotide polymorphism in the coding region of the human mu opioid receptor gene is the A118G variant, an adenine to guanine transition at nucleotide position 118 of the coding sequence of the gene. This polymorphism codes for an asparagine to aspartic acid substitution at amino acid 40 in the amino‐terminus, thereby removing a potential extracellular glycosylation site. Using in vitro cellular expression assays, this variant has been reported to change binding of the endogenous agonist beta‐endorphin and signaling of the receptor following binding of beta‐endorphin. Three clinical studies report that A118G genotype affects opioid antagonist‐mediated increases in cortisol levels. These studies demonstrate a functional role of this variant in responses to endogenous and exogenous opioids. To further characterize function, we expressed the prototype and variant receptors in two types of cells (human 293 embryonic kidney cells and Syrian hamster adenovirus‐12‐induced tumor cells). Stable expression of variant and prototype receptors was characterized by differences in levels of cell surface binding capacity (Bmax), forskolin‐induced cAMP accumulation, as well as agonist‐induced accumulation of cAMP (EC 50) for several agonists, but not for beta‐endorphin. In contrast, transiently expressed variant receptors showed only a minor difference in cell surface binding capacity compared to the prototype, and no differences in cAMP EC 50 values.
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“The A118G variant has enhanced binding and signaling properties, but low expression of mRNA (Zhang et al 2005; Kroslak et al 2007).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Kroslak et al 2007
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Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance
Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., Koch, T., Evans, C. J., & Christie, M. J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.005942 · Cited by 802
“However, the initial report of this variant affecting b-endorphin potency has not been replicated (Beyer et al., 2004; Kroslak et al., 2007).”
BackgroundMu Opioids and Their Receptors: Evolution of a Concept
Pasternak, G. W., & Pan, Y. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007138 · Cited by 582
“, 2008), and the A118G mutation altering glycosylation has been implicated in addiction (Bart et al., 2005; Kreek and LaForge, 2007; Kroslak et al., 2007).”
BackgroundInfluentialOpioid receptors: drivers to addiction?
Darcq, E., & Kieffer, B. L. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0028-x · Cited by 365
Davis, C. A., Levitan, R. D., Reid, C., Carter, J. C., Kaplan, A. S., Patte, K. A., King, N., Curtis, C., & Kennedy, J. L. (2009) · Obesity · doi:10.1038/oby.2009.52 · Cited by 314
“The rarer G118 allele has shown greater affinity for β-endorphin and morphine, but reduced mRNA and protein expression in vitro (22).”
BackgroundBurkett, J. P., & Young, L. J. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2794-x · Cited by 307
“The A118G variant has enhanced binding and signaling properties, but low expression of mRNA (Zhang et al. 2005; Kroslak et al. 2007).”
Metadata
- Authors
- Kroslak, T., LaForge, K. S., Gianotti, R. J., Ho, A., Nielsen, D. A., & Kreek, M. J.
- Affiliations
- Rockefeller University (US)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2007-06-03
- Volume
- 103
- Issue
- 1
- Pages
- 77-87
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2039877085
- Cited by
- 213
- References
- 42
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 9 · 2019: 8 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 16 · 2014: 21 · 2013: 17 · 2012: 23
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (C17893)
- National Institute on Drug Abuse (R01DA012848, P60 DA 05130, P60DA005130, R01-DA-12848)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- mu-opioid receptor, A118G polymorphism, single nucleotide polymorphisms, cAMP signaling, forskolin, cell surface binding
- MeSH terms
- Cyclic AMP, Analgesics, Opioid, Animals, Binding, Competitive, Cell Line, Cell Membrane, Dose-Response Relationship, Drug, Fibroblasts, Colforsin, Cricetinae, Humans, Kidney, Mesocricetus, Receptors, Opioid, mu, Gene Transfer Techniques, Polymorphism, Single Nucleotide, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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