Cited by 138Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeurotransmitter Receptor Influence on Behavior

A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases

Kurrasch‐Orbaugh, Deborah M., Parrish, Jason C., Watts, Val J., Nichols, David E.·2003·Journal of Neurochemistry

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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Crossref · 10.1046/j.1471-4159.2003.01921.x

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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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