The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
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]
Citations
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cPLA2 is phosphorylated and activated by MAP kinase
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Direct Stimulation of the Guanine Nucleotide Exchange Activity of p115 RhoGEF by Gα 13
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Nichols, D. E. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011478 · Cited by 1,762
“The PLA2 signaling pathway is more complex than the PI turnover cascade, apparently involving multiple G proteins and the extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogenactivated protein kinases (MAPKs), at least in NIH3T3 cells (Kurrasch-Orbaugh et al., 2003a).”
BackgroundSelf-citationNichols, D. E. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2003.11.002 · Cited by 1,211
Self-citationFunctional Selectivity and Classical Concepts of Quantitative Pharmacology
Urban, J. D., Clarke, W. P., von Zastrow, M., Nichols, D. E., Kobilka, B. K., Weinstein, H., Javitch, J. A., Roth, B. L., Christopoulos, A., Sexton, P. M., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.104463 · Cited by 1,119
“…it has been shown that AA signaling probably involves G i/o and G 12/13, as well as G , Rho, mitogen-activated protein kinase kinase 1/2, and p38 MAPK (Kurrasch-Orbaugh et al., 2003a), indicating that more than one signaling cascade is responsible for 5-HT2A receptor-mediated AA release.”
BackgroundInfluentialSelf-citationGonzález-Maeso, J., Weisstaub, N. V., Zhou, M., Chan, P., Ivic, L., Ang, R., Lira, A., Bradley-Moore, M., Ge, Y., Zhou, Q., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.008 · Cited by 925
Phospholipase A2 in the central nervous system
Sun, G. Y., Xu, J., Jensen, M. D., & Simonyi, Á. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r300016-jlr200 · Cited by 391
“PLA2 and AA release involved in both the Gi/o-associated G-mediated ERK1/2 and the G12/13-coupled, Rho-mediated p38 MAP kinase pathways (41, 42).”
Background
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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