Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons

Chen, Jingshan; Song, Jian; Yuan, Peixiong; Tian, Qingjun; Ji, Youngmi; Ren-Patterson, Renee F.; Liu, Guangping; Sei, Yoshitasu; Weinberger, Daniel R.

doi:10.1074/jbc.m111.262790

Cited by 72 publications

(59 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…COMT inhibitors are licensed as adjunctive therapy for Parkinson's disease and are under investigation in schizophrenia and other neuropsychiatric conditions (56,57). Extending earlier findings (19,20), our results show that COMT Val 158 Met genotype can affect the cognitive, behavioral, and perhaps affective responses to these drugs; genotype may also influence their toxicity (58). Thus, genotype will be worth measuring in the ongoing trials and including in the design of future ones.…”

Section: Discussionsupporting

confidence: 88%

COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

Farrell

Tunbridge

Braeutigam

et al. 2012

Biological Psychiatry

133

116

View full text Add to dashboard Cite

BackgroundCatechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val158Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.MethodsThirty-four COMT Met158Met (Met-COMT) and 33 COMT Val158Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task.ResultsIn the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences.ConclusionsDepending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.

show abstract

Section: Discussionsupporting

confidence: 88%

COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

Farrell

Tunbridge

Braeutigam

et al. 2012

Biological Psychiatry

133

116

View full text Add to dashboard Cite

show abstract

“…65 In brain, where MB-COMT activity is much higher, 66 this enzyme is located in the cell body, axons, and dendrites of cortical neurons. 67 Val158Met is a common functional single nucleotide substitution of COMT, 68 replacing methionine for valine at codon 158 of MB-COMT and at codon 108 of S-COMT. Via its effect on enzyme stability 69,70 the Met158 allele is three- to fourfold less active.…”

Section: Interplay Between Genetic and Enviromental Factorsmentioning

confidence: 99%

The Genetic Basis of Addictive Disorders

Ducci

Goldman

2012

Psychiatric Clinics of North America

221

172

View full text Add to dashboard Cite

“…COMT is present in either membrane bound form or in soluble form in peripheral tissues including liver and blood. While the soluble form is postulated to play a role in the detoxification and metabolism of catechols, the membrane bound form is majorly involved in dopamine degradation [6]. Several polymorphisms in the COMT gene have been reported.…”

Section: Introductionmentioning

confidence: 99%

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Singh¹,

Grover²,

Gupta³

et al. 2017

J Addict Res Ther

View full text Add to dashboard Cite

Alcohol dependence (AD), associated with high mortality and morbidity is caused due to involvement of both environmental and genetic factors. Behavioral effects of alcohol including cognitive impairment, motor incoordination, tolerance and dependence are likely due to its effect on the multiple brain proteins including neurotransmitters. Dysfunction in these neurotransmitter systems may be at the level of enzymes involved in metabolic degradation, or receptors involved in neurotransmission like dopamine, Gamma-amino butyric acid (GABA), serotonin etc. Genetic polymorphisms in these neurotransmitter systems are implicated in conferring susceptibility to AD. Aim:To identify association of single nucleotide polymorphisms (SNPs) in COMT (rs4680 and rs2075507) and GABAA receptor genes (rs13172914 and rs211014) with AD.Method: A total of 100 AD patients diagnosed on the basis of DSM IV criteria from the outpatient clinic of the National Drug Dependence Treatment Centre (NDDTC) of All India Institute of Medical Sciences (AIIMS), and 100 healthy individuals from the general population were recruited. A detailed history including pattern of drug use and demographic details with pedigree information was noted. Genomic DNA from peripheral blood samples was processed for PCR amplification followed by restriction digestion to screen for the presence of polymorphisms. Genotype and allele frequencies were evaluated and correlated with alcohol use parameters including duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and WHO ASSIST score and levels of liver function enzymes (SGPT and SGOT). Statistical analysis was performed using SPSS v21.0.Results: Genetic analysis of the study group revealed COMT rs4680 to be significantly associated with AD (p=0.03), while the other COMT SNP rs2075507 showed an association with increased levels of SGPT in the patients. GABAA receptor gene polymorphisms showed no association with AD. Conclusion:The study suggests a role of COMT gene polymorphism rs4680 in conferring susceptibility to AD.

show abstract

Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons

Cited by 72 publications

References 42 publications

COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

The Genetic Basis of Addictive Disorders

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Contact Info

Product

Resources

About