The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
Richard C Deth - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress in autism and its implications for dopamine stimulated Phospholipid Methylation
2010Co-Authors: Richard C Deth, Mostafa I Waly, Christina MuratoreAbstract:Neurons operate under unique redox conditions, increasing their vulnerability to oxidative stress, and recent studies provide evidence of oxidative stress and neuroinflammation in autism. Impaired Methylation is a consequence of oxidative stress, mediated in major part by inhibition of the folate- and colbalamin-dependent enzyme methionine synthase. Since methionine synthase activity is essential for dopamine-stimulated Phospholipid Methylation, some symptoms of autism may reflect impairment of this process. For example, dopamine D4 receptor activation plays an important role in gamma frequency synchronization of neural networks during attention, and autistic children display deficits in synchronization. This chapter reviews the metabolic events contributing to impaired Methylation and examines the mechanisms by which they may contribute to neurodevelopmental disorders such as autism.
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A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated Phospholipid Methylation
Journal of Computational Neuroscience, 2008Co-Authors: Anna Y. Kuznetsova, Richard C DethAbstract:We describe a new molecular mechanism of dopamine-induced membrane protein modulation that can tune neuronal oscillation frequency to attention-related gamma rhythm. This mechanism is based on the unique ability of D4 dopamine receptors (D4R) to carry out Phospholipid Methylation (PLM) that may affect the kinetics of ion channels. We show that by deceasing the inertia of the delayed rectifier potassium channel, a transition to 40 Hz oscillations can be achieved. Decreased potassium channel inertia shortens spike duration and decreases the interspike interval via its influence on the calcium-dependent potassium current. This mechanism leads to a transition to attention-related gamma oscillations in a pyramidal cell-interneuron network. The higher frequency and better synchronization is observed with PLM affecting pyramidal neurons only, and recurrent excitation between pyramidal neurons is important for synchronization. Thus dopamine-stimulated Methylation of membrane Phospholipids may be an important mechanism for modulating firing activity, while impaired Methylation can contribute to disorders of attention.
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protein kinase c regulates dopamine d4 receptor mediated Phospholipid Methylation
European Journal of Pharmacology, 2001Co-Authors: Alok Sharma, Mostafa I Waly, Richard C DethAbstract:Abstract Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent Phospholipid Methylation. To investigate possible regulation of this multi-step D4 receptor-mediated Phospholipid Methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [ 14 C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal Phospholipid Methylation and also shifted the dose–response curve for dopamine-stimulated Phospholipid Methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal Phospholipid Methylation but significantly inhibited dopamine-stimulated Phospholipid Methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated Phospholipid Methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated Phospholipid Methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated Phospholipid Methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N -nitro- l -arginine had any effect on basal or dopamine-stimulated Phospholipid Methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent Phospholipid Methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.
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relationship between dopamine stimulated Phospholipid Methylation and the single carbon folate pathway
Journal of Neurochemistry, 2001Co-Authors: Ren Zhao, Alok Sharma, Mostafa I Waly, Yuen Chen, Patrick J Stover, Andre Rosowsky, Barbara Malewicz, Richard C DethAbstract:In a previous study we demonstrated the ability of dopamine (DA) to stimulate Phospholipid Methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into Phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell Phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.
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d4 dopamine receptor mediated Phospholipid Methylation and its implications for mental illnesses such as schizophrenia
Molecular Psychiatry, 1999Co-Authors: Alok Sharma, M L Kramer, P F Wick, S Chari, S Shim, D Ouellette, M Nagata, C J Durand, M Kotb, Richard C DethAbstract:Previous studies have shown D2-like dopamine receptor involvement in the regulation of Phospholipid Methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [ 14 C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [ 3 H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to Phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.
L E Valladares - One of the best experts on this subject based on the ideXlab platform.
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Phospholipid Methylation decreases in human chorionic gonadotrophin induced desensitized rat leydig cells
Journal of Endocrinology, 1993Co-Authors: Ana Maria Ronco, L E ValladaresAbstract:: Phospholipid Methylation in Leydig cells from desensitized rats was studied. The incorporation of L-[methyl-3H]methionine into Phospholipids in intact Leydig cells decreased when animals were injected with a single high dose of human chorionic gonadotrophin (hCG). This effect was detected on the first day after hCG injection and remained up to 12 days after treatment. The inhibition was not due to a reduced uptake of L-[methyl-3H]methionine. A decreased Phospholipid Methylation with unaltered Phospholipid methyltransferase activity was observed on days 1, 6 and 12 after the hCG. On day 3 after hCG injection, Phospholipid methyltransferase activity and Phospholipid Methylation in intact Leydig cells were both inhibited by 40%. Also, a minimal amount of LH free receptors and the lowest number of total receptors was observed at this time. Thus, a relationship between the reduced enzymatic activity and the maximal decrease in LH surface receptors is suggested. In addition, the decreased incorporation of L-[methyl-3H]methionine into Phospholipids on days 1, 6 and 12 after hCG injection, could be associated with other cellular changes related to the desensitization process.
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human chorionic gonadotropin and free beta subunits stimulate Phospholipid Methylation in intact rat leydig cells
Steroids, 1993Co-Authors: Ana Maria Ronco, Miguel N Llanos, L E ValladaresAbstract:Abstract The effect of human chorionic gonadotropin (hCG) on intact Leydig cell Phospholipid Methylation was studied. Hormonal stimulation of rat Leydig cells increased the incorporation of [methyl- 3 H]methionine into Phospholipids threefold. This effect was observed after 10 minutes of incubation time and was time and dose dependent with a maximal stimulation at 67 ng/ml of hCG. In the presence of hCG, 3 H-labeled methyl groups were preferentially incorporated into phosphatidyl-N-monomethylethanolamine. This effect of hCG was not reproduced by dibutyryl cyclic adenosine monophosphate (cAMP), cholera toxin, or forskolin. Purified hCGβ subunit but not hCGα subunit had stimulatory activity on Leydig cell Phospholipid Methylation. We conclude that luteinizing hormone (LH)/hCG stimulates specifically Leydig cell Phospholipid Methylation, because LH-releasing hormone or [Arg 8 -vasopressin did not modify these reactions. We postulate that these reactions are occurring at a cellular level that involves hormone-receptor interaction. It is also suggested that this biological response involves hCGβ subunit receptor interaction and does not require cAMP synthesis.
Alok Sharma - One of the best experts on this subject based on the ideXlab platform.
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protein kinase c regulates dopamine d4 receptor mediated Phospholipid Methylation
European Journal of Pharmacology, 2001Co-Authors: Alok Sharma, Mostafa I Waly, Richard C DethAbstract:Abstract Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent Phospholipid Methylation. To investigate possible regulation of this multi-step D4 receptor-mediated Phospholipid Methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [ 14 C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal Phospholipid Methylation and also shifted the dose–response curve for dopamine-stimulated Phospholipid Methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal Phospholipid Methylation but significantly inhibited dopamine-stimulated Phospholipid Methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated Phospholipid Methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated Phospholipid Methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated Phospholipid Methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N -nitro- l -arginine had any effect on basal or dopamine-stimulated Phospholipid Methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent Phospholipid Methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.
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relationship between dopamine stimulated Phospholipid Methylation and the single carbon folate pathway
Journal of Neurochemistry, 2001Co-Authors: Ren Zhao, Alok Sharma, Mostafa I Waly, Yuen Chen, Patrick J Stover, Andre Rosowsky, Barbara Malewicz, Richard C DethAbstract:In a previous study we demonstrated the ability of dopamine (DA) to stimulate Phospholipid Methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into Phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell Phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.
-
d4 dopamine receptor mediated Phospholipid Methylation and its implications for mental illnesses such as schizophrenia
Molecular Psychiatry, 1999Co-Authors: Alok Sharma, M L Kramer, P F Wick, S Chari, S Shim, D Ouellette, M Nagata, C J Durand, M Kotb, Richard C DethAbstract:Previous studies have shown D2-like dopamine receptor involvement in the regulation of Phospholipid Methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [ 14 C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [ 3 H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to Phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.
Ana Maria Ronco - One of the best experts on this subject based on the ideXlab platform.
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Phospholipid Methylation decreases in human chorionic gonadotrophin induced desensitized rat leydig cells
Journal of Endocrinology, 1993Co-Authors: Ana Maria Ronco, L E ValladaresAbstract:: Phospholipid Methylation in Leydig cells from desensitized rats was studied. The incorporation of L-[methyl-3H]methionine into Phospholipids in intact Leydig cells decreased when animals were injected with a single high dose of human chorionic gonadotrophin (hCG). This effect was detected on the first day after hCG injection and remained up to 12 days after treatment. The inhibition was not due to a reduced uptake of L-[methyl-3H]methionine. A decreased Phospholipid Methylation with unaltered Phospholipid methyltransferase activity was observed on days 1, 6 and 12 after the hCG. On day 3 after hCG injection, Phospholipid methyltransferase activity and Phospholipid Methylation in intact Leydig cells were both inhibited by 40%. Also, a minimal amount of LH free receptors and the lowest number of total receptors was observed at this time. Thus, a relationship between the reduced enzymatic activity and the maximal decrease in LH surface receptors is suggested. In addition, the decreased incorporation of L-[methyl-3H]methionine into Phospholipids on days 1, 6 and 12 after hCG injection, could be associated with other cellular changes related to the desensitization process.
-
human chorionic gonadotropin and free beta subunits stimulate Phospholipid Methylation in intact rat leydig cells
Steroids, 1993Co-Authors: Ana Maria Ronco, Miguel N Llanos, L E ValladaresAbstract:Abstract The effect of human chorionic gonadotropin (hCG) on intact Leydig cell Phospholipid Methylation was studied. Hormonal stimulation of rat Leydig cells increased the incorporation of [methyl- 3 H]methionine into Phospholipids threefold. This effect was observed after 10 minutes of incubation time and was time and dose dependent with a maximal stimulation at 67 ng/ml of hCG. In the presence of hCG, 3 H-labeled methyl groups were preferentially incorporated into phosphatidyl-N-monomethylethanolamine. This effect of hCG was not reproduced by dibutyryl cyclic adenosine monophosphate (cAMP), cholera toxin, or forskolin. Purified hCGβ subunit but not hCGα subunit had stimulatory activity on Leydig cell Phospholipid Methylation. We conclude that luteinizing hormone (LH)/hCG stimulates specifically Leydig cell Phospholipid Methylation, because LH-releasing hormone or [Arg 8 -vasopressin did not modify these reactions. We postulate that these reactions are occurring at a cellular level that involves hormone-receptor interaction. It is also suggested that this biological response involves hCGβ subunit receptor interaction and does not require cAMP synthesis.
Mostafa I Waly - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress in autism and its implications for dopamine stimulated Phospholipid Methylation
2010Co-Authors: Richard C Deth, Mostafa I Waly, Christina MuratoreAbstract:Neurons operate under unique redox conditions, increasing their vulnerability to oxidative stress, and recent studies provide evidence of oxidative stress and neuroinflammation in autism. Impaired Methylation is a consequence of oxidative stress, mediated in major part by inhibition of the folate- and colbalamin-dependent enzyme methionine synthase. Since methionine synthase activity is essential for dopamine-stimulated Phospholipid Methylation, some symptoms of autism may reflect impairment of this process. For example, dopamine D4 receptor activation plays an important role in gamma frequency synchronization of neural networks during attention, and autistic children display deficits in synchronization. This chapter reviews the metabolic events contributing to impaired Methylation and examines the mechanisms by which they may contribute to neurodevelopmental disorders such as autism.
-
protein kinase c regulates dopamine d4 receptor mediated Phospholipid Methylation
European Journal of Pharmacology, 2001Co-Authors: Alok Sharma, Mostafa I Waly, Richard C DethAbstract:Abstract Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent Phospholipid Methylation. To investigate possible regulation of this multi-step D4 receptor-mediated Phospholipid Methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [ 14 C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal Phospholipid Methylation and also shifted the dose–response curve for dopamine-stimulated Phospholipid Methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal Phospholipid Methylation but significantly inhibited dopamine-stimulated Phospholipid Methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated Phospholipid Methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated Phospholipid Methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated Phospholipid Methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N -nitro- l -arginine had any effect on basal or dopamine-stimulated Phospholipid Methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent Phospholipid Methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.
-
relationship between dopamine stimulated Phospholipid Methylation and the single carbon folate pathway
Journal of Neurochemistry, 2001Co-Authors: Ren Zhao, Alok Sharma, Mostafa I Waly, Yuen Chen, Patrick J Stover, Andre Rosowsky, Barbara Malewicz, Richard C DethAbstract:In a previous study we demonstrated the ability of dopamine (DA) to stimulate Phospholipid Methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into Phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell Phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.