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A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases
Abstract
Previous studies in our laboratory have shown that in NIH3T3-5HT2A cells, 5-HT-induced AA release is PLA2-coupled and independent of 5-HT2A receptor-mediated PLC activation. Although 5-HT2A receptor-mediated PLC activation is known to be Galphaq-coupled, much less is understood about 5-HT2A receptor-mediated PLA2 activation. Therefore, the studies presented here were aimed at elucidating the signal transduction pathway linking stimulation of the 5-HT2A receptor to PLA2 activation. By employing various selective inhibitors, toxins, and antagonistic peptide constructs, we propose that the 5-HT2A receptor can couple to PLA2 activation through two parallel signaling cascades. Initial experiments were designed to examine the role of pertussis toxin-sensitive G proteins, namely Galphai/o, as well as pertussis toxin-insensitive G proteins, namely Galpha12/13, in 5-HT-induced AA release. Furthermore, inactivation of both Gbetagamma heterodimers and Rho proteins resulted in decreased agonist-induced AA release, without having any effect on PLC-IP accumulation. We also demonstrated 5-HT2A receptor-mediated phosphorylation of ERK1,2 and p38. Moreover, pretreatment with selective ERK1,2 and p38 inhibitors resulted in decreased 5-HT-induced AA release. Taken together, these results suggest that the 5-HT2A receptor expressed in NIH3T3 cells can couple to PLA2 activation though a complex signaling mechanism involving both Galphai/o-associated Gbetagamma-mediated ERK1,2 activation and Galpha12/13-coupled, Rho-mediated p38 activation.
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“Via activation of 5-HT2AR, psychedelics activate intracellular signaling pathways such as PLC, PLA, and Src (88–90).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [88]
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Metadata
- Authors
- Kurrasch‐Orbaugh, D. M., Parrish, J. C., Watts, V. J., & Nichols, D. E.
- Affiliations
- Purdue University West Lafayette (US)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2003-07-21
- Volume
- 86
- Issue
- 4
- Pages
- 980-991
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1523962342
- Cited by
- 138
- References
- 56
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 9 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DA 02189)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- phospholipase A2 activation, arachidonic acid release, mitogen-activated protein kinase, ERK1/2, p38 MAPK, Gα12/13, Gαi/o, Rho proteins, signal transduction, pertussis toxin
- MeSH terms
- Animals, Enzyme Activation, Enzyme Inhibitors, Fibroblasts, Inositol Phosphates, Type C Phospholipases, Phospholipases A, Receptors, Serotonin, Signal Transduction, 3T3 Cells, Arachidonic Acid, GTP-Binding Proteins, Mitogen-Activated Protein Kinase 1, Enzyme Activators, rho GTP-Binding Proteins, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Receptor, Serotonin, 5-HT2A, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Mice, Phospholipases A2
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