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PubMed1995

Hydrogen peroxide (H2O2) production by monoamine oxidase in rat tissues using endogenous catecholamines as substrates. A comparison of catalytic monoamine oxidase histochemistry and recently published catechol-O-methyltransferase immunohistochemistry.

Histochemical studies on hydrogen peroxide (H2O2) production by monoamine oxidase (MAOX) using xenobiotic (foreign) catecholamines such as tryptamine or tyramine as substrates may not reveal the true H2O2-production capacity of this enzyme and the potential co-localization and cooperation of MAOX with catechol-O-methyltransferase (COMT), the other catecholamine-degrading enzyme. Therefore, in the present study the catecholamine hormones adrenaline (epinephrine) and noradrenaline (norepinephrine) and the catecholamine neurotransmitter noradrenaline as well as the COMT metabolites metanephrine and normetanephrine, which are likely to be the more important MAOX substrates, were used for MAOX visualization in many rat tissues with a cerium-diaminobenzidine-H2O2-Co method. Adrenaline and noradrenaline were autooxidized by Ce3+ and could not be employed; with metanephrine or normetanephrine as substrates MAOX produced considerable amounts of H2O2 in many cells and tissues. Comparisons with immunohistochemical COMT-data for rats from the literature show that MAOX and COMT are co-localized or not. Therefore, different from our current knowledge in rats COMT and MAOX either co-operate in catecholamine degradation or they degrade the respective catecholamines alone.

Animals↗
PubMed2001

Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease.

BACKGROUND: When levodopa therapy is used in Parkinson's disease, degradation of the drug in the peripheral nervous system is associated with dyskinesias and motor fluctuations. Much of this degradation is produced by catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines and catechol compounds. Inhibition of COMT activity prolongs the action of levodopa and reduces fluctuations in response. Entacapone is a selective inhibitor of COMT whose activity is primarily in the peripheral nervous system, with little effect in the central nervous system. OBJECTIVE: This paper reviews the pharmacologic properties and clinical usefulness of entacapone in the treatment of Parkinson's disease. METHODS: Recent studies, abstracts, and reviews published in the English-language literature were identified through searches of MEDLINE (1966-September 2000), International Pharmaceutical Abstracts (1970-September 2000), and PharmaProjects (September 2000 version), and from the Web sites of Parkinson's disease conferences held from 1996 to September 2000. Relevant human studies provided further information on the pharmacologic properties and clinical usefulness of entacapone. RESULTS: Entacapone is rapidly absorbed, with a time to maximum concentration of approximately 1 hour. Its plasma elimination half-life is 0.4 to 0.7 hour in the beta phase and 2.4 hours in the gamma phase, and it has 35% absolute bioavailability after oral administration, secondary to first-pass clearance. Entacapone is 98% protein bound; thus, it is not distributed widely in tissues and is almost completely metabolized before excretion (0.1%-0.2% of dose unchanged in urine). The drug inhibits erythrocyte-soluble COMT activity in a dose-dependent fashion (48% after a 400-mg dose, 82% after an 800-mg dose). The inhibitory effect is reversible, with recovery of soluble COMT activity within 4 to 8 hours. In levodopa-treated patients with Parkinson's disease who experience motor fluctuations, clinical trials have demonstrated entacapone's effectiveness in increasing "on" time (the period during which medications relieve the symptoms of Parkinson's disease) by up to 1.2 hours, decreasing "off" time (the period during which symptoms increase) by 0.9 to 1.3 hours, and producing overall total improvement in scores on the Unified Parkinson's Disease Rating Scale. The recommended dosage of entacapone is 200 mg administered orally with each dose of levodopa/carbidopa, up to 8 doses per day. The drug is generally well tolerated, with most adverse effects attributed to levodopa-related dopaminergic effects, including dyskinesias and nausea. CONCLUSIONS: In clinical trials, adjuvant treatment with entacapone appeared to be an effective and well-tolerated therapeutic strategy in patients with Parkinson's disease who experience fluctuations in the response to levodopa therapy. The increased elimination half-life of levodopa with concomitant entacapone results in greater and more sustained plasma levodopa levels, with more constant dopaminergic stimulation in the brain and greater amelioration of parkinsonian symptoms.

Antiparkinson Agents↗
PubMed1997

Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior.

We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).

Adult↗
PubMed2001

Significance of the catechol-O-methyltransferase gene polymorphism in migraine.

The objective was to assess the significance of the catechol-o-methyltransferase (COMT) enzyme polymorphism in migraine. For this reason, 62 migraineurs and 64 healthy volunteers were included in the study. The analysis of COMT polymorphism was performed using PCR. The H/H genotype was more frequent in the control group than in the patients group (P=0.032). The homozygous or heterozygous L allele was over represented in the migraineurs compared with the controls (P=0.013). The L/L genotype was over represented in the migraineurs who also had a family history of migraine (P=0.003). There was no relationship between aura and COMT genotypes. In conclusion, the COMT polymorphism may be of potential pharmacological importance regarding the individual differences in the metabolism of catechol drugs in migraineurs. Although altered catecholamine activity due to polymorphism of COMT gene may be one of the mechanisms involved in the pathogenesis of migraine, these mechanisms are not related to presence or absence of aura.

Adult↗
PubMed2000

Progression of human breast cancers to the metastatic state is linked to genotypes of catechol-O-methyltransferase.

There is increasing evidence that catecholestrogens may contribute to the development of breast cancer. Specifically, inactivation of catecholestrogens may prevent the genesis and arrest the progression of the disease. Catechol-O-methyltransferase (COMT), Glutathione S-transferase (GST) M1 and GSTP1 are responsible for the detoxification of catecholestrogens, and are polymorphic in the human population. In this study, a PCR-based restriction fragment length polymorphism analysis was performed to determine genotypes of the COMT, GSTM1 and GSTP1 genes. We investigated the relationship between the germline polymorphism of these genes and clinico-pathological characteristics in 140 patients with breast cancer. Among 73 patients with the low activity COMT allele, 49 (67%) had regional lymph node metastasis. On the other hand, only 27 (40%) of 67 patients without the low activity allele had lymph node metastasis. The COMT genotype was significantly associated with clinical stage and the extent of regional lymph node metastasis of breast cancer (P<0.05). However, polymorphisms of the GSTM1 and GSTP1 gene were not associated with clinico-pathological factors. Our findings suggest that the allele encoding for low activity COMT may contribute to the progression of breast cancer.

Adult↗
PubMed1997

Increase of catechol-O-methyltransferase activity in rat brain microglia after intrastriatal infusion of fluorocitrate, a glial toxin.

Striatal catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B; an astroglial enzyme), alkaline phosphodiesterase I (PDE; a microglia/macrophage marker) and tyrosine hydroxylase (TH; catecholaminergic neuron marker) activities were analyzed biochemically 1-3 days after infusion of fluorocitrate, an astrocyte damaging agent. Astrocytes, microglia and neurons were stained immunohistochemically with specific antibodies (against glial fibrillary acidic protein, OX-42 and TH, respectively) and with COMT antiserum. Three days after fluorocitrate infusion the activity of MAO-B was reduced, whereas COMT and PDE activities were increased. The elevation of COMT immunoreactivity co-localized to microglial cells, but not to astrocytes. In conclusion, this is the first report indicating that microglia contains COMT activity which may be increased in pathological conditions.

Animals↗
PubMed1975

Affinity labeling of catechol O-methyltransferase by N-haloacetyl derivatives of 3,5-dimethoxy-4-hydroxyphenylethylamine and 3,4-dimethoxy-5-hydroxyphenylethylamine. Kinetics of inactivation.

In an attempt to elucidate the relationship between the chemical structure and the catalytic function of catechol O-methyltransferase (COMT), several classes of affinity labeling reagents have been synthesized and their interaction with COMT has been studied. Earlier studies have shown that various N-haloacetyl derivatives of 3,5-dimethoxy-4-hydroxyphenylethylamine were effective affinity labeling reagents for this enzyme. In this report we have shown that N-haloacetyl derivatives of the isomeric 3,4-dimethoxy-5-hydroxyphenylethylamine also rapidly and irreversibly inactivate COMT ant they satisfy many of the criteria established for affinity labeling reagents. This latter group of agents appear to modify a nucleophilic residue at the active site of COMT different from that modified by the 3,5-dimethoxy-4-hydroxyphenylethylamine series. Evidence to support this conclusion has been obtained by comparing the kinetics of COMT inactivation and the substrate protection profiles for these two classes of affinity labeling reagents.

Animals↗
PubMed1996

17 beta-estradiol metabolism by hamster hepatic microsomes: comparison of catechol estrogen O-methylation with catechol estrogen oxidation and glutathione conjugation.

Catechol estrogens, the cytochromes P450 mediated metabolites of 17 beta-estradiol, undergo further metabolism either via catechol O-methyltransferase (COMT) catalyzed methylation, or by oxidation and subsequent thioether formation with glutathione (GSH). Secondary metabolites of 17 beta-estradiol arising from both these metabolic pathways have been identified in vivo. However, the relative contribution of catechol O-methylation, and catechol oxidation followed by GSH conjugation, to the disposition of the catechol estrogens is unclear. We have therefore quantified both pathways of catechol estrogen disposition, generated in situ from 17 beta-estradiol, in hamster hepatic microsomes. 17 beta-Estradiol was readily converted to 2- and 4-hydroxy-17 beta-estradiol, both of which were effectively methylated in the presence of COMT (300 units/mL). Addition of GSH (50 microM-1 mM) to microsomal incubations resulted in the formation of four catechol estrogen-derived GSH conjugates. Three conjugates of 2-hydroxy-17 beta-estradiol were identified: 2-hydroxy-1,4-bis(glutathione-S-yl)-17 beta-estradiol, 2-hydroxy-1-glutathione-S-yl-17 beta-estradiol, and 2-hydroxy-4-glutathione-S-yl-27 beta-estradiol. In contrast, just one GSH conjugate of 4-hydroxy-17 beta-estradiol was identified: 4-hydroxy-1-glutathione-S-yl-17 beta-estradiol. When a combination of COMT and GSH were simultaneously added to microsomal incubations, both metabolic pathways competed for the same pool of catechol estrogens, and ascorbate dramatically influenced which of these two pathways predominate. In the presence of ascorbate, catechol estrogen methylation predominated over catechol estrogen oxidation and GSH conjugation. In the absence of ascorbic acid, catechol estrogen methylation, and catechol estrogen oxidation inked to GSH conjugation, contributed equally to the disposition of the catechol estrogens. 17 beta-Estradiol 2- and 4-hydroxylase activity was always higher in the absence of ascorbate, irrespective of whether GSH or COMT was used as the trapping agent. Thus, the usual method (COMT plus ascorbate) of determining 17 beta-estradiol 2- and 4-hydroxylase activity underestimates enzyme activity by approximately 50% when compared to the value obtained when GSH is used to trap the o-quinones in the absence of ascorbate. A reassessment of 17 beta-estradiol 2- and 4-hydroxylase activity in different species and tissues is required to permit a more informed evaluation of the role of catechol estrogens in estrogen-induced carcinogenesis.

Animals↗
PubMed1999

Catechol-O-methyltransferase activity in CHO cells expressing norepinephrine transporter.

1. We examined the existence of catecholamine metabolizing enzymes (catechol-O-methyltransferase, COMT, and monoamine oxidase, MAO) in CHO cells transfected with norepinephrine (NE) transporter (NET) cDNA. 2. NET activity was studied by incubating cells with [3H]-NE (0. 5 microCi ml-1, 20 min) in a Na+ containing medium. Incubation with [3H]-NE lead to [3H] accumulation at 47797+/-4864 d.p.m. per well. Specific inhibitors of NET abolished this uptake. 3. During post-uptake incubation, [3H] leaked rapidly from cells and the extracellular phase comprised 89% of total radioactivity within 40 min. Both [3H] retention and [3H] 'leakage' were largely unaffected by inhibitors for MAO. In contrast, COMT inhibitors, U-0521 and Ro 41-0960, dose-dependently increased intracellular [3H]-NE retention with a maximal increase of 4.5 fold. The EC50 for Ro 41-0960 was 139-times lower than that of U-0521. U-0521 largely inhibited [3H] 'leakage' and doubled the apparent Vmax for [3H]-NE uptake. 4. Addition of U-0521 during uptake incubation increased intracellular NE content by 8 fold. Normetanephrine, the COMT-dependent metabolite of NE, was formed in large quantities during post-uptake incubation. U-0521 significantly inhibited the formation of NMN with an equal preservation of intracellular NE. 5. CHO cells expressing NET possess COMT activity, which is responsible for the metabolism of NE to form lipophilic metabolite normetanephrine. The apparent 'properties' of the NET function expressed in CHO cells changed, after inhibition of COMT, in such a way closer to that described in the native neuronal preparations.

Animals↗
PubMed2004

Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes.

Catechol O-methyltransferase (COMT) plays an important role in the metabolism of catecholamines, catecholestrogens and catechol drugs. A common COMT G472A genetic polymorphism (Val108/158Met) that was identified previously is associated with decreased levels of enzyme activity and has been implicated as a possible risk factor for neuropsychiatric disease. We set out to 'resequence' the human COMT gene using DNA samples from 60 African-American and 60 Caucasian-American subjects. A total of 23 single nucleotide polymorphisms (SNPs), including a novel nonsynonymous cSNP present only in DNA from African-American subjects, and one insertion/deletion were observed. The wild type (WT) and two variant allozymes, Thr52 and Met108, were transiently expressed in COS-1 and HEK293 cells. There was no significant change in level of COMT activity for the Thr52 variant allozyme, but there was a 40% decrease in the level of activity in cells transfected with the Met108 construct. Apparent K(m) values of the WT and variant allozymes for the two reaction cosubstrates differed slightly, but significantly, for 3,4-dihydroxybenzoic acid but not for S-adenosyl-L-methionine. The Met108 allozyme displayed a 70-90% decrease in immunoreactive protein when compared with WT, but there was no significant change in the level of immunoreactive protein for Thr52. A significant decrease in the level of immunoreactive protein was also observed in hepatic biopsy samples from patients homozygous for the allele encoding Met108. These observations represent steps toward an understanding of molecular genetic mechanisms responsible for variation in COMT level and/or properties, variation that may contribute to the pathophysiology of neuropsychiatric disease.

Animals↗
PubMed2005

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow.

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [(15)O]H(2)O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

Adult↗
PubMed2006

Tolcapone improves cognition and cortical information processing in normal human subjects.

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

Adult↗
PubMed1997

Metabolism of catecholamines by catechol-O-methyltransferase in cells expressing recombinant catecholamine transporters.

To determine if catechol-O-methyltransferase (COMT) metabolizes catecholamines within cell lines used for heterologous expression of plasmalemmal transporters and alters the measured characteristics of 3H-substrate transport, the uptake of monoamine transporter substrates was assessed in three cell lines (C6 glioma, L-M fibroblast, and HEK293 cells) that had been transfected with the recombinant human transporters. Uptake and cellular retention of 3H-catecholamines was increased by up to fourfold by two COMT inhibitors, tropolone and Ro 41-0960, with potencies similar to those for inhibition of COMT activity, whereas the uptake of two transporter substrates that are not substrates for COMT, [3H]serotonin and [3H]MPP+, was unaffected. Direct measurement of monoamine substrates by HPLC confirmed that tropolone (1 mM) increased the retention of the catecholamines dopamine and norepinephrine, but not the retention of serotonin in HEK293 cells. Saturation analysis of the uptake of [3H]dopamine by C6 cells expressing the dopamine transporter demonstrated that tropolone (1 mM) decreased the apparent Km of transport from 0.61 microM to 0.34 microM without significantly altering the maximal velocity of transport. These data suggest that endogenous COMT activity in mammalian cells may alter neurotransmitter deposition and thus the apparent kinetic characteristics of transport.

Carrier Proteins↗
PubMed2000

5-hydroxyconiferyl aldehyde modulates enzymatic methylation for syringyl monolignol formation, a new view of monolignol biosynthesis in angiosperms.

S-Adenosyl-L-methionine-dependent caffeate O-methyltransferase (COMT, EC 2.1.1.6) has traditionally been thought to catalyze the methylation of caffeate and 5- hydroxyferulate for the biosynthesis of syringyl monolignol, a lignin constituent of angiosperm wood that enables efficient lignin degradation for cellulose production. However, recent recognition that coniferyl aldehyde prevents 5-hydroxyferulate biosynthesis in lignifying tissue, and that the hydroxylated form of coniferyl aldehyde, 5-hydroxyconiferyl aldehyde, is an alternative COMT substrate, demands a re-evaluation of the role of COMT during monolignol biosynthesis. Based on recombinant aspen (Populus tremuloides) COMT enzyme kinetics coupled with mass spectrometry analysis, this study establishes for the first time that COMT is in fact a 5-hydroxyconiferyl aldehyde O-methyltransferase (AldOMT), and that 5-hydroxyconiferyl aldehyde is both the preferred AldOMT substrate and an inhibitor of caffeate and 5-hydroxyferulate methylation, as measured by K(m) and K(i) values. 5-Hydroxyconiferyl aldehyde also inhibited the caffeate and 5-hydroxyferulate methylation activities of xylem proteins from various angiosperm tree species. The evidence that syringyl monolignol biosynthesis is independent of caffeate and 5-hydroxyferulate methylation supports our previous discovery that coniferyl aldehyde prevents ferulate 5-hydroxylation and at the same time ensures a coniferyl aldehyde 5-hydroxylase (CAld5H)-mediated biosynthesis of 5-hydroxyconiferyl aldehyde. Together, our results provide conclusive evidence for the presence of a CAld5H/AldOMT-catalyzed coniferyl aldehyde 5-hydroxylation/methylation pathway that directs syringyl monolignol biosynthesis in angiosperms.

Acrolein↗
PubMed1996

Characterization of the rat catechol-O-methyltransferase gene proximal promoter: identification of a nuclear protein-DNA interaction that contributes to the tissue-specific regulation.

The methylating enzyme catechol-O-methyltransferase (COMT) is an important inactivator of substrates containing catechol-structure, such as catechol neurotransmitters and hormones. In previous studies, the rat COMT gene has been cloned and characterized, and it has been shown that the two COMT polypeptides, S- and MB-COMT, are expressed from one gene by cooperation of two separate promoters. One promoter, P2, functions constitutively, whereas the other, the proximal P1 promoter, is regulated in a tissue-specific manner. In this report, a more detailed analysis of the rat P1 promoter is presented. By using reporter gene constructs, it is shown that upstream sequences of the P1 promoter contain several regions that modulate the expression either positively or negatively. These experiments also show that the region between the MB- and S-ATG translation initiation codons is indispensable for the activity of this promoter. Analysis of this region by DNase I footprinting and gel retardation assays identified the presence of several DNA elements with SP1 and NF1 recognition site homologies that bound both liver and brain nuclear proteins. However, one 11-nucleotide-long DNA region containing an overlapping consensus binding sequence for CREB and C/EBP-like factors reacted only with the liver nuclear lysate. Supershift experiments suggest that the transcription factor C/EBPalpha mediates the tissue-specific expression of the rat COMT P1 promoter.

Animals↗
PubMed2003

Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk.

Estrogen is involved in breast carcinogenesis. Hypotheses have been raised that its effect is modified by enzymes such as catechol-O-methyltransferase (COMT) that deactivate potentially genotoxic estrogen metabolites. We have investigated the association between the functional genetic Val108/158Met polymorphism in COMT and breast cancer risk in a large population-based case-control study performed in the genetically homogeneous Swedish population. We determined COMT genotype in 1534 women with invasive breast cancer and in 1504 control women and calculated odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models. There was no overall association between COMT genotype and breast cancer risk. However, the L allele was associated with an increased risk for lobular breast cancer, with OR 2.0 (95% CI 1.2-3.5) for HL and 1.7 (95% CI 0.9-3.0) for LL. In exploratory subset analyses, we found no statistically significant interaction, but some indication of a positive association between HL and LL genotypes and breast cancer among women with diabetes mellitus and a negative association among nulliparous women. Based on our findings, COMT activity alone does not seem to play a major role in breast carcinogenesis, but may be of importance in certain histotypes or in conjunction with other exposures.

Aged↗
PubMed2000

Genetic modifiers of the Drosophila NSF mutant, comatose, include a temperature-sensitive paralytic allele of the calcium channel alpha1-subunit gene, cacophony.

The N-ethylmaleimide-sensitive fusion protein (NSF) has been implicated in vesicle trafficking in perhaps all eukaryotic cells. The Drosophila comatose (comt) gene encodes an NSF homolog, dNSF1. Our previous work with temperature-sensitive (TS) paralytic alleles of comt has revealed a function for dNSF1 at synapses, where it appears to prime synaptic vesicles for neurotransmitter release. To further examine the molecular basis of dNSF1 function and to broaden our analysis of synaptic transmission to other gene products, we have performed a genetic screen for mutations that interact with comt. Here we report the isolation and analysis of four mutations that modify TS paralysis in comt, including two intragenic modifiers (one enhancer and one suppressor) and two extragenic modifiers (both enhancers). The intragenic mutations will contribute to structure-function analysis of dNSF1 and the extragenic mutations identify gene products with related functions in synaptic transmission. Both extragenic enhancers result in TS behavioral phenotypes when separated from comt, and both map to loci not previously identified in screens for TS mutants. One of these mutations is a TS paralytic allele of the calcium channel alpha1-subunit gene, cacophony (cac). Analysis of synaptic function in these mutants alone and in combination will further define the in vivo functions and interactions of specific gene products in synaptic transmission.

Alleles↗
PubMed2004

Genetic basis for individual variations in pain perception and the development of a chronic pain condition.

Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.

Adolescent↗