Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use.
Abstract
Fatty acid amide hydrolase (FAAH) inactivates the endogenous cannabinoid (endocannabinoid) anandamide and related lipid transmitters in vivo. A single nucleotide polymorphism (SNP) in the human FAAH gene (385C to A) has recently been described that, in homozygous form, is over-represented in subjects with problem drug use. This SNP, which converts a conserved proline residue in FAAH to threonine (P129T), suggests a potential role for the FAAH-endocannabinoid system in regulating addictive behavior. Nonetheless, the impact of the 385A mutation on the biochemical and cellular function of FAAH remains unknown. Here, we report that T-lymphocytes isolated from patients homozygous for the P129T-FAAH variant express less than half of the FAAH protein and activity observed in wild-type (WT) lymphocytes. Transfected COS-7 cells also expressed significantly lower levels of P129T-FAAH compared with WT-FAAH, indicating that the aberrant expression of the former protein is not a cell type-specific phenomenon. A comparison of the transcription/translation efficiencies and cellular stabilities of WT- and P129T-FAAH proteins revealed that the reduced expression of the mutant enzyme is due to a post-translational mechanism that precedes productive folding. These findings indicate that the natural 385A SNP in the human FAAH gene produces a mutant enzyme with reduced cellular stability, thus fortifying a potential link between functional abnormalities in the endocannabinoid system and drug abuse and dependence.
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The variation C385A in FAAH reduces both the enzyme's expression and its activity.
“The variation C385A in FAAH reduces both the enzyme’s expression and its activity 80”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [80]
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- Authors
- Chiang, K. P.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Chiang, K. P.
- ORCID
- Chiang, K. P.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-07-21
- Volume
- 13
- Issue
- 18
- Pages
- 2113-2119
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2157501942
- Cited by
- 278
- References
- 29
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 16 · 2023: 16 · 2022: 12 · 2021: 11 · 2020: 16 · 2019: 15 · 2018: 11 · 2017: 13 · 2016: 13 · 2015: 21 · 2014: 13 · 2013: 9 · 2012: 15
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (5r01da015749-03)
- National Institute on Drug Abuse (DA013173, R01DA013173, DA-017259, DA015749, P01DA017259)
- National Center for Research Resources (M01RR000833, M0-1RR00833)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- fatty acid amide hydrolase, single nucleotide polymorphisms, endocannabinoid system, anandamide, problematic substance use, drug addiction, T cells, protein stability, post-translational regulation, enzyme expression, addictive behavior
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Amino Acid Sequence, Animals, Chlorocebus aethiops, Half-Life, Humans, Molecular Sequence Data, Mutation, Protein Conformation, T-Lymphocytes, Transfection, Gene Expression, COS Cells, Substance-Related Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Cannabinoid Receptor Modulators, Endocannabinoids
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