A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression

Samuvel, Devadoss J.; Jayanthi, Lankupalle D.; Bhat, Narayan R.; Ramamoorthy, Sammanda

doi:10.1523/jneurosci.3754-04.2005

Cited by 198 publications

(284 citation statements)

References 61 publications

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“…All three monoamine transporters are regulated by p38 MAPK (1,23,52). In support of this, we found evidence for the association of phospho-p38 MAPK with NET, SERT, and DAT.…”

Section: Discussionsupporting

confidence: 79%

“…Dopamine transporter (DAT) polyclonal antibody was from Santa Cruz Biotechnology Inc. (Dallas, TX). Polyclonal antibodies to NET and serotonin transporter (SERT) were generated and characterized in the laboratory (1,23). Antibody to p38 MAPK was from Santa Cruz Biotechnology Inc. Phospho-p38 MAPK antibody was purchased from Cell Signal Technology (Danvers, MA).…”

Section: Methodsmentioning

confidence: 99%

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A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

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Background: Cocaine-activated p38 MAPK-mediated norepinephrine transporter (NET) threonine 30 phosphorylation up-regulates NET. Results: p38 MAPK inhibition and TAT-NET-Thr 30 peptide blocks cocaine-mediated NET up-regulation and cocaine-induced locomotor sensitization and conditioned place preference (CPP). Conclusion: Blockade of p38 MAPK-mediated Thr30 -dependent NET regulation attenuates cocaine-induced locomotor sensitization, CPP, and CPP reinstatement. Significance: Regulation of NET plays a mechanistic role in cocaine-mediated behaviors.

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“…All three monoamine transporters are regulated by p38 MAPK (1,23,52). In support of this, we found evidence for the association of phospho-p38 MAPK with NET, SERT, and DAT.…”

Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

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“…This pathway has previously been implicated in the acute regulation of SERT activity in vitro [27,45,46] and in vivo [28,47,48]. Our data presented here suggest that p38 MAPK is also involved in the chronic regulation of SERT activity upon pro-longed cytokine exposure.…”

Section: Discussionsupporting

confidence: 67%

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

et al. 2013

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Pro-inflammatory cytokines have been implicated in the precipitation of depression and related disorders, and the antidepressant sensitive serotonin transporter (SERT) may be a major target for immune regulation in these disorders. Here, we focus on astrocytes, a major class of immune competent cells in the brain, to examine the effects of pro-longed treatment with tumor necrosis factoralpha (TNF-a) on SERT activity. We first established that high-affinity serotonin uptake into C6 glioma cells occurs through a SERT-dependent mechanism. Functional SERT expression is also confirmed for primary astrocytes. In both cell types, exposure to TNF-a resulted in a dose-and timedependent increase in SERT-mediated 5-HT uptake, which was sustained for at least 48 h post-stimulation. Further analysis in primary astrocytes revealed that TNF-a enhanced the transport capacity (V max ) of SERT-specific 5-HT uptake, suggesting enhanced transporter expression, consistent with our observation of an increase in SERT mRNA levels. We confirmed that in both, primary astrocytes and C6 glioma cells, treatment with TNF-a activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment with the p38 MAPK inhibitor SB203580 attenuated the TNF-a mediated stimulation of 5-HT transport in both, C6 glioma and primary astrocytes. In summary, we show that SERT gene expression and activity in astrocytes is subject to regulation by TNF-a, an effect that is at least in part dependent on p38 MAPK activation.

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“…15 Fluoxetine also activates the p38 MAPK cascade, 80 suggesting that the depressive symptoms observed in n-3 PUFA deprived rats are related to decreased p38 MAPK activity. Constitutive p38 MAPK activity maintains the expression of rat brain dopamine 81,82 and serotonin transporters 83 and n-3 PUFA deprivation upregulates D1 and D2 receptors 84 and decreases stimulated serotonin release, 85 all of which are believed to be involved in depression.…”

Section: Discussionmentioning

confidence: 99%

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

et al. 2006

Mol Psychiatry

258

151

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Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.

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A Role for p38 Mitogen-Activated Protein Kinase in the Regulation of the Serotonin Transporter: Evidence for Distinct Cellular Mechanisms Involved in Transporter Surface Expression

Abstract: The serotonin transporter (SERT) is regulated by various signaling mechanisms that may operate to maintain appropriate levels of synaptic serotonin (5-HT). We demonstrate that one of the mitogen-activated protein kinases (MAPKs), p38 MAPK, regulates SERT.

Cited by 198 publications

References 61 publications

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

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