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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

Academic Article
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Overview

related to degree

  • Chiang, Kyle Ping, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2001 - 2006

authors

  • Chiang, Kyle Ping
  • Gerber, A. L.
  • Sipe, J. C.
  • Cravatt, Benjamin

publication date

  • September 2004

journal

  • Human Molecular Genetics  Journal

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.

subject areas

  • Amidohydrolases
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cannabinoid Receptor Modulators
  • Cercopithecus aethiops
  • Endocannabinoids
  • Gene Expression
  • Half-Life
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Polymorphism, Single Nucleotide
  • Proteasome Endopeptidase Complex
  • Protein Conformation
  • Substance-Related Disorders
  • T-Lymphocytes
  • Transfection
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Identity

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddh216

PubMed ID

  • 15254019
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Additional Document Info

start page

  • 2113

end page

  • 2119

volume

  • 13

issue

  • 18

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