Membrane bound catechol-O-methytransferase is the dominant isoform for dopamine metabolism in PC12 cells and rat brain

Su, Yu-Pin; DePasquale, Michael; Liao, Gangling; Buchler, Ingrid P.; Zhang, Gongliang; Byers, Spencer; Carr, Gregory V.; Barrow, James C.; Wei, Huijun

doi:10.1016/j.ejphar.2021.173909

Cited by 15 publications

(8 citation statements)

References 23 publications

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“…18 S-COMT is mainly located in the cytosolic fraction of the periphery, and MB-COMT is considered to be more important in the central nervous system. 19 To differentiate between the interaction of celastrol with S-COMT and MB-COMT, we knocked down the expression of endogenous COMTs in HeLa S3 cells and observed the change in fluorescence signal as a result of C1a labeling. Both expressions of MB-COMT and S-COMT decreased, which led to a decrease in fluorescent intensity after probe labeling (Figure 2B).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Both COMTs catalyze the regioselective transfer of a methyl group from S-adenosyl methionine (SAM) to one hydroxyl group of its catechol substrates such as dopamine . S-COMT is mainly located in the cytosolic fraction of the periphery, and MB-COMT is considered to be more important in the central nervous system . To differentiate between the interaction of celastrol with S-COMT and MB-COMT, we knocked down the expression of endogenous COMTs in HeLa S3 cells and observed the change in fluorescence signal as a result of C1a labeling.…”

Section: Resultsmentioning

confidence: 99%

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Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor

et al. 2022

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Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear. Here, we used multiple mass-spectrometry-based approaches to identify catechol-O-methyltransferase (COMT) as a major binding target of celastrol and characterized their interaction comprehensively. Celastrol was found to inhibit the enzymatic activity of COMT and increased the dopamine level in neuroendocrine chromaffin cells significantly. Our study not only revealed a novel binding target of celastrol but also provided a new scaffold and cysteine hot spot for developing new generation COMT inhibitors in combating neurological disorders.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor

et al. 2022

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“…It has been shown that PC12 cells, a rat adrenal pheochromocytoma‐derived cell line, express all key regulators of dopaminergic function, including MB‐COMT and S‐COMT (Zhang et al, 2019). Another study conducted by this team demonstrated that deletion of MB‐COMT using CRISPR‐cas9 technology or inhibition of MB‐COMT activity using an MB‐COMT selective inhibitor decreased dopamine metabolite levels, which suggests that this form of COMT plays the main role in dopamine biotransformation (Su et al, 2021). Kim et al (2014) showed that DEPs increase dopamine levels and decrease its metabolites [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in PC12 cells, indicating that DEPs may inhibit COMT activity, which is in agreement with our results.…”

Section: Discussionmentioning

confidence: 99%

Nitrophenols disrupt the expression and activity of biotransformation enzymes (CYP3A and COMT) in chicken ovarian follicles in vivo and in vitro

Kozubek,

Katarzyńska‐Banasik,

Kowalik

et al. 2024

J of Applied Toxicology

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Nitrophenols are environmental pollutants and xenobiotics, the main sources of which are diesel exhaust fumes and pesticides. The biotransformation processes that take place in the liver are defence mechanisms against xenobiotics, such as nitrophenols. Our previous study showed that the chicken ovary is an additional xenobiotic detoxification place and that nitrophenols disrupt steroidogenesis in chicken ovarian follicles. Therefore, the present study aimed to determine the in vivo and in vitro effects of 4‐nitrophenol (PNP) and 3‐methyl‐4‐nitrophenol (PNMC) on the expression and activity of phase I (CYP3A) and phase II (COMT) biotransformation enzymes in chicken ovary. In an in vivo study, hens were treated with a vehicle or 10 mg PNP or PNMC/kg b.wt. per day for 6 days. In an in vitro study, prehierarchical white and yellowish follicles, as well as the granulosa and theca layers of the three largest preovulatory follicles (F3, F2 and F1), were isolated and then incubated in a control medium or medium supplemented with PNP (10−6 M) or PNMC (10−6 M) for 24 or 48 h. Both in vivo and in vitro studies showed that nitrophenols exert tissue‐ and compound‐dependent (PNP or PNMC) effects on CYP3A and COMT gene (real‐time PCR) protein (Western blot) expression and their activity (colorimetric methods). The inhibitory effect of nitrophenols in vivo on the activity of biotransformation enzymes suggest that the ovary has the capacity to metabolise PNP and PNMC.

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“…These cells express both the NE transporter Sl6a2 and monoamine oxidase A Maoa; and deleting Slc6a2 in SAMs increased thermogenesis and prevented DIO similar to our knockout mice 58 . The role of the catecholamine transporters is controversial, however, as another group has published that a different transporter OCT3 (Slc22a3) is involved in NE uptake into adipocytes 59 , and the cytoplasmic form of the enzyme catecholamine-O-methyl transferase (S-COMT) is largely responsible for peripheral metabolism of catecholamines 60 . Interestingly, Comt is a target for PPAR and pioglitazone treatment increases COMT expression, reduces plasma catecholamines, and improves glucose tolerance in rats 61 and COMT (Val158Met) genotype is associated with abdominal obesity and a predilection for unhealthy foods in humans 62,63 .…”

Section: Discussionmentioning

confidence: 99%

Gnas ablation in CD11c+ cells prevents high-fat diet-induced obesity by elevating adipose tissue catecholamine levels and thermogenesis

Zeng

Herdman

Lee

et al. 2022

Preprint

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CD11c+ immune cells are a potential therapeutic target for treatment of obesity-related insulin resistance and type 2 diabetes (T2D). In obesity, CD11c+ immune cells are recruited to white adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. In this study, we found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from high-fat diet-induced obesity, glucose intolerance and insulin resistance. GnasΔCD11c mice (KO) had increased oxygen consumption, energy expenditure, and beigeing of white adipose tissue (WAT). Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and the absence of T and B cells by crossing the KO to a Rag1-/- background did not alter the phenotype. Notably, we observed elevated norepinephrine and elevated cAMP signaling in the WAT of KO mice. The KO adipose tissue also had reduced expression of catecholamine transport and degradation enzymes. Collectively, our results identified an important role of Gαs in CD11c+ cells in whole body metabolism regulation by controlling norepinephrine levels in WAT, modulating catecholamine-induced lipolysis and increasing thermogenesis that together created a lean phenotype.

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Membrane bound catechol-O-methytransferase is the dominant isoform for dopamine metabolism in PC12 cells and rat brain

Cited by 15 publications

References 23 publications

Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor

Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor

Nitrophenols disrupt the expression and activity of biotransformation enzymes (CYP3A and COMT) in chicken ovarian follicles in vivo and in vitro

Gnas ablation in CD11c+ cells prevents high-fat diet-induced obesity by elevating adipose tissue catecholamine levels and thermogenesis

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