P38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process

Zhu, Chong-Bin; Carneiro, Ana M.; Dostmann, Wolfgang R.; Hewlett, William A.; Blakely, Randy D.

doi:10.1074/jbc.m410858200

Cited by 228Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchIon Transport and Channel Regulation

P38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process

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Zhu, Chong-Bin, Carneiro, Ana M., Dostmann, Wolfgang R., Hewlett, William A., Blakely, Randy D.·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m410858200

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Abstract

Presynaptic, plasma membrane serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) clear 5-HT following vesicular release and are regulated through trafficking-dependent pathways. Recently, we provided evidence for a trafficking-independent mode of SERT regulation downstream of adenosine receptor (AR) activation that is sensitive to p38 MAPK inhibitors. Here, we probe this pathway in greater detail, demonstrating elevation of 5-HT transport by multiple p38 MAPK activators (anisomycin, H(2)O(2), and UV radiation), in parallel with p38 MAPK phosphorylation, as well as suppression of anisomycin stimulation by p38 MAPK siRNA treatments. Studies with transporter-transfected Chinese hamster ovary cells reveal that SERT stimulation is shared with the human norepinephrine transporter but not the human dopamine transporter. Saturation kinetic analyses of anisomycin-SERT activity reveal a selective reduction in 5-HT K(m) supported by a commensurate increase in 5-HT potency (K(i)) for displacing surface antagonist binding. Anisomycin treatments that stimulate SERT activity do not elevate surface SERT surface density whereas stimulation is lost with preexposure of cells to the surface-SERT inactivating reagent, 2-(trimethylammonium)ethyl methane thiosulfonate. Guanylyl cyclase (1H-(1,2,4)-oxadiazolo[4,3-a]-quinoxalin-1-one) and protein kinase G inhibitors (H8, DT-2) block AR stimulation of SERT yet fail to antagonize SERT stimulation by anisomycin. We thus place p38 MAPK activation downstream of protein kinase G in a SERT-catalytic regulatory pathway, distinct from events controlling SERT surface density. In contrast, the activity of protein phosphatase 2A inhibitors (fostriecin and calyculin A) to attenuate anisomycin stimulation of 5-HT transport suggests that protein phosphatase 2A is a critical component of the pathway responsible for p38 MAPK up-regulation of SERT catalytic activity.

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Inflammatory cytokines including IL-6 increase 5-HTT expression and function, an effect mediated by induction of p38 MAPK both in vitro and in vivo.
“Interestingly, inflammatory cytokines, including IL-6, have been shown to increase 5-HTT expression and function (Morikawa et al., 1998, Mossner et al., 1998, Sakai et al., 2003, Tsao et al., 2008) (see Figure 1), an effect found to be mediated by induction of p38 mitogen-activated protein kinase (MAPK), both in vitro and in vivo (Zhu et al., 2005, Zhu et al., 2006, Zhu et al., 2010a).”
From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Zhu et al., 2005
Cytokines influence the synthesis of monoamines through disruption of tetrahydrobiopterin.
“Cytokines also influence the synthesis of monoamines through disruption of tetrahydrobiopterin, an essential enzyme co-factor to hydroxylases involved in monoamine synthesis.”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [90]
Cytokines can modulate serotonin signaling by increasing the expression and function of monoamine transporters.
“Furthermore, they can modulate serotonin signaling by increasing the expression and function of monoamine transporters which perform the re-uptake of synaptic serotonin (89–92).”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [90]

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Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer
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Altered Expression of Genes Involved in Inflammation and Apoptosis in Frontal Cortex in Major Depression
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Cytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise
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Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression
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Cytokines and Glucocorticoid Receptor Signaling
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Interleukin-1 Receptor Activation by Systemic Lipopolysaccharide Induces Behavioral Despair Linked to MAPK Regulation of CNS Serotonin Transporters
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Kinase cascades and ligand-directed signaling at the kappa opioid receptor
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p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1
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Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression
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Role of Inflammation in Suicide: From Mechanisms to Treatment
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Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase
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The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction
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The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases
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Going with the Flow: Trafficking‐Dependent and ‐Independent Regulation of Serotonin Transport
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The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes
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STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior
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Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models
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Modulation of the trafficking of the human serotonin transporter by human alpha‐synuclein
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Single Molecule Analysis of Serotonin Transporter Regulation Using Antagonist-Conjugated Quantum Dots Reveals Restricted, p38 MAPK-Dependent Mobilization Underlying Uptake Activation
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Pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT in rheumatoid arthritis and the new anti-depression drugs
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p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse
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Brain Cytokines and the 5‐HT System during Poly I:C‐Induced Fatigue
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Authors: Zhu, C.-B., Carneiro, A. M., Dostmann, W. R., Hewlett, W. A., & Blakely, R. D.
Affiliations: Vanderbilt University (US)
University of Vermont (US)
Corresponding author: Blakely, Randy D.
ORCID: Zhu, Chong-Bin
Carneiro, Ana M.
Blakely, Randy D.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2005-04
Volume: 280
Issue: 16
Pages: 15649-15658
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m410858200
OpenAlex: W2124241220
Cited by: 228
References: 70
Citations by year: 2026: 4 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 8 · 2018: 11 · 2017: 5 · 2016: 13 · 2015: 15 · 2014: 12 · 2013: 17 · 2012: 20
FWCI: 5.18
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5677 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Vanderbilt University
National Institutes of Health
National Heart, Lung, and Blood Institute (HL 68991, R01HL068991)
National Institute of Mental Health (T32MH065782, T32-MH65782-02)
National Institute on Drug Abuse (DA-07390, R01DA007390)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords: serotonin transporter, p38 MAPK, protein phosphatase 2A, anisomycin, adenosine receptors, protein kinase G, norepinephrine transporter, dopamine transporter, guanylyl cyclase inhibition, H8
MeSH terms: Animals, Cell Membrane, Cricetinae, Humans, Membrane Glycoproteins, Nerve Tissue Proteins, Phosphoprotein Phosphatases, Serotonin, Enzyme Activators, Membrane Transport Proteins, p38 Mitogen-Activated Protein Kinases, Serotonin Plasma Membrane Transport Proteins, Protein Phosphatase 2

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P38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process

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