Metabolism of Catecholamines by Catechol‐<i>O</i>‐Methyltransferase in Cells Expressing Recombinant Catecholamine Transporters

Eshleman, Amy J.; Stewart, Emilie; Evenson, Anna K.; Mason, John N.; Blakely, Randy D.; Janowsky, Aaron; Neve, Kim A.

doi:10.1046/j.1471-4159.1997.69041459.x

Cited by 43 publications

(46 citation statements)

References 17 publications

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“…Average levels of dopamine and serotonin in FBS present in cell cultures over 24 h were probably even lower than initial levels; recent experiments have shown that catechol-O-methyltransferase actively degrades monoamines in several cell cultures expressing recombinant DAT cDNA (Eshleman et al, 1997). In any case, as shown in Fig.…”

Section: Effects Of Cocainementioning

confidence: 78%

Cocaine Induction of Dopamine Transporter Trafficking to the Plasma Membrane

Little

Elmer²,

Zhong³

et al. 2002

Mol Pharmacol

139

107

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Little et al., 1993Little et al., , 1999Staley et al., 1994), accompanied by up-regulation of dopamine uptake (Mash et al., 1997). Such functional alterations could be important, perhaps contributing to cocaine-induced binging, withdrawal symptoms, or craving. Beyond drug self-administration, dopamine neurons play a role in other rewarding phenomena, including sex (Everitt, 1990) and eating (Phillips et al., 1993), suggesting that regulatory alterations in DAT function could have interesting implications for understanding the dynamics of a number of motivational and appetitive processes. Recent experiments in cell culture have determined that phosphorylative treatments (Pristupa et al., 1998;Daniels et al., 1999;Melikian and Buckley, 1999) or exposure to the stimulant d-amphetamine (Saunders et al., 2000) dynamically regulate DAT function by changing DAT cellular localization, perhaps invoking mechanisms that might be related to those activated by cocaine.Understanding the mechanisms involved in DAT binding site changes is important because 1) binding site alterations are the primary alterations documented in postmortem brain from cocaine users; 2) DAT inhibitors/ligands are being developed extensively as both therapeutic and imaging agents for both the DAT as well as dopamine neurons; and 3) DAT regulation may provide broader insights into the pharmacological effects of drugs on transporter binding sites. In addition to our need to uncover cocaine's neurochemical effects that provoke symptoms associated with its dependence, it is possible that new therapeutic or imaging agents (many of which are often DAT uptake inhibitors) might themselves induce adaptations in DAT function, as well as alter cocaine's effect on dopamine uptake. Also, potentially, DAT inhibitor binding sites could be altered through some mechanism that is independent of changes in DAT concentration or function.

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Section: Effects Of Cocainementioning

confidence: 78%

Cocaine Induction of Dopamine Transporter Trafficking to the Plasma Membrane

Little

Elmer²,

Zhong³

et al. 2002

Mol Pharmacol

139

107

View full text Add to dashboard Cite

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“…The resulting pellet was then resuspended in 3 ml of buffer and homogenized with a Polytron homogenizer at setting 7 for 5 to 10 s. The assays contained approximately 75 to 150 g of membrane protein for DHTB binding (less than 15% of the radioactivity added was bound), or 25 to 50 g of membrane protein for RTI-55 binding (less than 25% of radioactivity added was bound), drug, and jpet.aspetjournals.org methyl transferase (COMT) inhibitor] were included in the buffer so that results could be compared with studies done using tissue from animals, which require the addition of MAO and COMT inhibitors. In previous studies, Vindis et al (2000) found no evidence for MAO activity in HEK-293 cells; however, other studies suggest the presence of COMT activity in HEK-293 cells (Eshleman et al, 1997). Pifl et al (1995) using African green monkey kidney (COS-7) cells, in the absence of MAO or COMT inhibitors, reported that 70 to 80% of the tritium released from hDAT cells and 80 to 90% of the tritium released from hDAT/rVMAT2 cells was [ 3 H]DA, suggesting that DA metabolites comprise only a small part of the recovered tritium.…”

Section: Materials [mentioning

confidence: 86%

Effects of Methamphetamine and Lobeline on Vesicular Monoamine and Dopamine Transporter-Mediated Dopamine Release in a Cotransfected Model System

Wilhelm¹,

Johnson²,

Lysko³

et al. 2004

J Pharmacol Exp Ther

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Dopamine (DA) retention and drug-induced release kinetics were characterized in human embryonic kidney (HEK)-293 cells stably coexpressing the human DA transporter (hDAT) and human vesicular monoamine transporter (hVMAT2 These results suggest that coexpression of the hDAT and hVMAT2 can be used as a model system to distinguish functional pools of DA and to quantify differences in drug effects on DA disposition. In addition, cotransfected cells can be used to determine mechanisms of simultaneous drug interactions at multiple sites.All drugs of abuse, including METH, either directly or indirectly increase DA neurotransmission (Grace, 2000;Di Chiara, 2002). The DAT and VMAT2 terminate neurotransmission after stimulated release by reuptake and repackaging of DA into vesicles. The interaction of these proteins in a simple, stable system has not been described in detail. However, Pifl et al. (1995), using a superfusion apparatus, reported increases in DA uptake and amphetamine-induced release of [ 3 H]DA in cells coexpressing the hDAT and rat (r)VMAT2, compared with cells expressing only the hDAT. There was also an apparent decrease in the potency and efficacy of amphetamine-induced release from DAT cells versus hDAT/rVMAT2 cells, although no direct comparisons were made. METH is an efficacious and relatively potent releaser of DA and preloaded 1-methyl-4-phenylpyridinium via the hDAT (Eshleman et al., 1994;Sulzer et al., 1995;Johnson et al., 1998;Dwoskin and Crooks, 2002). The amphetamines exert their actions through a number of mechanisms, including inhibition of reuptake, redistribution of DA between vesicle stores and cytoplasm, reversal of transport, and possibly by collapsing proton gradients driving vesicular uptake (Cubells et al

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“…Furthermore, chronic antidepressant treatment has been shown to increase the expression and release of glial cell-derived neurotrophic factor (GDNF) (33)(34)(35). Curiously, the molecular entities most commonly associated with antidepressants, serotonin and norepinephrine transporters, are not endogenously expressed in C6 cells (36), which still respond to antidepressants by mediating lipid raft translocation of G␣ s .…”

Section: Discussionmentioning

confidence: 99%

Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs

Erb¹,

Schappi

Rasenick

2016

Journal of Biological Chemistry

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Depression is a significant public health problem for which currently available medications, if effective, require weeks to months of treatment before patients respond. Previous studies have shown that the G protein responsible for increasing cAMP (G␣ s ) is increasingly localized to lipid rafts in depressed subjects and that chronic antidepressant treatment translocates G␣ s from lipid rafts. Translocation of G␣ s , which shows delayed onset after chronic antidepressant treatment of rats or of C6 glioma cells, tracks with the delayed onset of therapeutic action of antidepressants. Because antidepressants appear to specifically modify G␣ s localized to lipid rafts, we sought to determine whether structurally diverse antidepressants accumulate in lipid rafts. Sustained treatment of C6 glioma cells, which lack 5-hydroxytryptamine transporters, showed marked concentration of several antidepressants in raft fractions, as revealed by increased absorbance and by mass fingerprint. Closely related molecules without antidepressant activity did not concentrate in raft fractions. Thus, at least two classes of antidepressants accumulate in lipid rafts and effect translocation of G␣ s to the non-raft membrane fraction, where it activates the cAMP-signaling cascade. Analysis of the structural determinants of raft localization may both help to explain the hysteresis of antidepressant action and lead to design and development of novel substrates for depression therapeutics.Depression is the leading cause of long term disability in the industrialized world (1). Although depression is a significant health problem in the United States and antidepressants are heavily prescribed (2), the mechanism of action for these drugs is not understood. Further, nearly a third of those treated with these drugs do not achieve remission of their depression (3). Although most of these drugs do interfere with monoamine uptake or catabolism, they exert this effect within hours, even though most of the compounds require weeks before alleviation of symptoms is observed (4). Thus, other targets for antidepressant drugs may exist (4).Chronic antidepressant treatment engages signaling pathways apart from increasing monoamine density in the synaptic cleft. One of these is an increased accumulation of cellular cAMP and sequelae thereof, such as increased cAMP-response element-binding protein (CREB) phosphorylation and increased transcription of cAMP-regulated genes (e.g. BDNF) (5). Moreover, positron emission tomography (PET) evidence suggests that cAMP is diminished throughout the brain of depressed human subjects (6). Thus, it is possible that some antidepressant effects are mediated through induction of the cAMP-generating system, including G␣ s and adenylyl cyclase.Previous studies demonstrated that chronic antidepressant treatment translocates G␣ s from lipid rafts, whereupon it engages in a more facile activation of adenylyl cyclase (7,8). Lipid rafts are regions of the plasma membrane rich in caveolin, cholesterol, sphingolipids, and cytoskeletal an...

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Metabolism of Catecholamines by Catechol‐O‐Methyltransferase in Cells Expressing Recombinant Catecholamine Transporters

Cited by 43 publications

References 17 publications

Cocaine Induction of Dopamine Transporter Trafficking to the Plasma Membrane

Cocaine Induction of Dopamine Transporter Trafficking to the Plasma Membrane

Effects of Methamphetamine and Lobeline on Vesicular Monoamine and Dopamine Transporter-Mediated Dopamine Release in a Cotransfected Model System

Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs

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