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p38 MAPK Activation Elevates Serotonin Transport Activity via a Trafficking-independent, Protein Phosphatase 2A-dependent Process
Open accessAbstract
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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“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
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“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]
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“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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Cytokines sing the blues: inflammation and the pathogenesis of depression
Raison, C. L., Capuron, L., & Miller, A. H. (2006) · Trends in Immunology · doi:10.1016/j.it.2005.11.006 · Cited by 3,009
Immune system to brain signaling: Neuropsychopharmacological implications
Capuron, L., & Miller, A. H. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.014 · Cited by 1,195
Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications
Felger, J. C., & Lotrich, F. E. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.04.060 · Cited by 1,180
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Miller, A. H., Haroon, E., Raison, C. L., & Felger, J. C. (2013) · Depression and Anxiety · doi:10.1002/da.22084 · Cited by 892
Metadata
- 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.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 280
- Issue
- 16
- Pages
- 15649-15658
- ISSN
- 0021-9258 (ISSN-L)
- 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
- 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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