Disease relevance of FAAH

• A clinical study performed on 100 healthy women showed that a low FAAH activity in lymphocytes correlates with spontaneous abortion, whereas anandamide transporter and cannabinoid receptors in these cells remain unchanged [1].
• An FAAH activity sharing several biochemical properties with the human brain enzyme was demonstrated in human neuroblastoma CHP100 and lymphoma U937 cells [2].
• Recombinant forms of WT- and DeltaTM-FAAH expressed and purified from Escherichia coli exhibited essentially identical enzymatic properties which were also similar to those of the native enzyme from rat liver [3].
• Previous research has described the impact of cannabis consumption on pregnancy, potential roles of endocannabinoids and abnormalities of FAAH expression in recurrent miscarriage and pregnancy [4].
• The cannabinergic proteins currently being explored, which include the CB1 and CB2 receptors, FAAH and the anandamide transporter, are excellent targets for the development of therapeutically useful drugs for a range of conditions including pain, loss of appetite, immunosuppression, peripheral vascular disease and motor disorders [5].

Psychiatry related information on FAAH

• Collectively, these results suggest that genetic mutations in FAAH may constitute important risk factors for problem drug use and support a potential link between functional abnormalities in the endogenous cannabinoid system and drug abuse and dependence [6].
• 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 [7].
• As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH [8].
• Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains [9].

High impact information on FAAH

• Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy [10].
• CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids [11].
• RESULTS: CB1r and FAAH were localized in the dorsal vagal complex, consisting of the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem [12].
• Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase [13].
• Moreover, systemic administration of AM404 to either wild-type or FAAH(-/-) mice enhanced the hypothermic effects of exogenous anandamide, a response that was prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A) [14].

Chemical compound and disease context of FAAH

• These data: (a) provide the first evidence that cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including emesis, via downstream metabolites produced independently of FAAH [15].
• Since the anti-apoptotic activity of leptin and progesterone parallels their effect on FAAH, it can be suggested that enhanced degradation of AEA is the means to protect U937 cells against the toxicity of this compound [16].
• Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH) [17].

Biological context of FAAH

• This single nucleotide polymorphism results in a missense mutation (385C-->A) that converts a conserved proline residue to threonine (Pro129-->Thr), producing a FAAH variant that displays normal catalytic properties but an enhanced sensitivity to proteolytic degradation [6].
• Analysis of the FAAH promoter showed an Ikaros binding site, and mutation of this site prevented FAAH activation by progesterone in transient expression assays [18].
• Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational levels and involved binding of leptin to its receptor with an apparent dissociation constant (K(d)) of 1.95 +/- 0.14 nm and maximum binding (B(max)) of 392 +/- 8 fmol x mg protein(-1) [19].
• Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level and was specific [18].
• Furthermore, the effect of progesterone on FAAH promoter was additive to that of physiological amounts of leptin, which binds to a cAMP response element-like site in the promoter region [18].

Anatomical context of FAAH

• 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 [7].
• 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 [7].
• At variance with FAAH, the lymphocyte anandamide transporter and cannabinoid receptors were not affected by treatment with progesterone or cytokines [1].
• Here, we show that FAAH is expressed throughout the human first trimester placenta, in extravillous trophoblast columns, villous cytotrophoblasts, syncytiotrophoblasts, and macrophages [20].
• A mutant form of the rat FAAH protein lacking this N-terminal transmembrane domain (DeltaTM-FAAH) was generated and, like wild type FAAH (WT-FAAH), was found to be tightly associated with membranes when expressed in COS-7 cells [3].

Associations of FAAH with chemical compounds

• Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of (-)-Delta9-tetrahydrocannabinol (THC; the major psychoactive constituent of marijuana), due to enhanced signaling via CB1 [21].
• Good FAAH substrates such as anandamide and 2-arachidonoylglycerol inhibited the release of leukemia-inhibitory factor from human lymphocytes, but N-palmitoylethanolamine, a poor substrate, did not [1].
• Human chorionic gonadotropin or cortisol had no effect on FAAH activity [1].
• Thus, FAAH inhibition in mouse brain does not appear to be a primary target for organophosphorus pesticide-induced neurotoxic action (cholinergic or intermediate syndrome or delayed neurotoxicity) [22].
• Ovariectomy prevented the decrease in FAAH, and both progesterone and estrogen further reduced its basal levels, suggesting hormonal control of the enzyme [23].
• Yet it has been suggested that FAAH functions in vivo only as an anandamide-degrading enzyme because its pharmacological and genetic inactivation is usually accompanied by elevation of anandamide, but not 2-AG, levels [24].

Enzymatic interactions of FAAH

• The characterization, cloning, and neuronal distribution of FAAH have been detailed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as the endogenous ligand for the cannabinoid receptor [25].

Other interactions of FAAH

• Analysis of the FAAH promoter showed a cAMP-response element-like site, which is a transcriptional target of STAT3 [19].
• Our observations demonstrate that genetic variations in TRPA1, COMT, and FAAH contribute gender specifically to individual variations in short duration cold pain sensitivity in a European American cohort [26].
• Further study in European American subjects found significant associations between short duration cold pain sensitivity and variations in TRPA1, COMT, and FAAH in a gender dependent manner [26].
• We show that, unlike CB1R and PLD, the activity of AMT and the activity and expression of FAAH increase while the endogenous levels of AEA decrease in HaCaT and NHEK cells induced to differentiate in vitro by 12-O-tetradecanoylphorbol 13-acetate (TPA) plus calcium [27].
• The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros [18].

Analytical, diagnostic and therapeutic context of FAAH

• Analysis of the oligomerization states of WT- and DeltaTM-FAAH by chemical cross-linking, sedimentation velocity analytical ultracentrifugation, and size exclusion chromatography indicated that both enzymes were oligomeric when membrane-bound and after solubilization [3].
• Additionally, SDS-PAGE analysis of the recombinant proteins identified the presence of SDS-resistant oligomers for WT-FAAH, but not for DeltaTM-FAAH [3].
• The human FAAH gene was mapped to region 1p34-p35, closely linked to D1S197 and D1S443, by using PCR analysis of somatic cell hybrid (SCH) and radiation hybrid mapping panels [28].
• We have examined CB1 receptor and FAAH expression in human term placenta by immunohistochemistry [4].
• These data, corroborated by transient expression and electrophoretic mobility-shift assays, demonstrate an unprecedented cell-specific regulation of the FAAH gene, which has important implications for the control of tone and activity of AEA along the neuroimmune axis [29].

References