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

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

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

DOI 10.1046/j.1471-4159.2003.01921.x

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1046/j.1471-4159.2003.01921.x

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).
Hoyer, D., Clarke, D. E., Fozard, J. R., Hartig, P. R., Martin, G. R., Mylecharane, E. J., Saxena, P. R., & Humphrey, P. P. A. (1994) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06783-3 · Cited by 3,025
Changes in the Levels of Inositol Phosphates after Agonist-Dependent Hydrolysis of Membrane Phosphoinositides
Berridge, M. J., Dawson, R. M. C., Downes, C. P., Heslop, J. P., & Irvine, R. F. (1983) · Biochemical Journal · doi:10.1042/bj2120473 · Cited by 1,954
cPLA2 is phosphorylated and activated by MAP kinase
Lin, L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., & Davis, R. J. (1993) · Cell · doi:10.1016/0092-8674(93)90666-e · Cited by 1,851
A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP
Clark, J. D., Lin, L.-L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., & Knopf, J. L. (1991) · Cell · doi:10.1016/0092-8674(91)90556-e · Cited by 1,688
Direct modification of the membrane adenylate cyclase system by islet-activating protein due to ADP-ribosylation of a membrane protein.
Katada, T., & Ui, M. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.10.3129 · Cited by 811
Direct Stimulation of the Guanine Nucleotide Exchange Activity of p115 RhoGEF by Gα 13
Hart, M. J., Jiang, X., Kozasa, T., Roscoe, W., Singer, W. D., Gilman, A. G., Sternweis, P. C., & Bollag, G. E. (1998) · Science · doi:10.1126/science.280.5372.2112 · Cited by 780
Regulatory Functions of Phospholipase A2
Murakami, M., Nakatani, Y., Atsumi, G., Inoue, K., & Kudo, I. (1997) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v17.i3-4.10 · Cited by 542
Asparagine residue in the rho Gene Product Is the Modification Site for Botulinum ADP-ribosyltransferase
Sekine, A., Fujiwara, M., & Narumiya, S. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)81834-8 · Cited by 541
Phosphorylation and activation of a high molecular weight form of phospholipase A2 by p42 microtubule-associated protein 2 kinase and protein kinase C.
Nemenoff, R. A., Winitz, S., Qian, N. X., Putten, V. V., Johnson, G. L., & Heasley, L. E. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53948-x · Cited by 522
Cytosolic phospholipase A2.
Clark, J., Schievella, A., Nalefski, E. A., & Lin, L. (1995) · Journal of Lipid Mediators and Cell Signalling · doi:10.1016/0929-7855(95)00012-f · Cited by 515

Show all 56 references

Sorted by citations

Psychedelics
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-citation
Hallucinogens
Nichols, D. E. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2003.11.002 · Cited by 1,211
Self-citation
Functional 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-citation
Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior
González-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
The role of serotonin 5-HT2A receptors in memory and cognition
Zhang, G., & Stackman, R. W. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00225 · Cited by 398
“5-HT2AR activation also stimulates the Gα12/13-phospholipase A2 signal transduction pathway, which promotes arachidonic acid release (Kurrasch-Orbaugh et al., 2003a,b).”
Background
Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders
Farooqui, A. A., Ong, W., & Horrocks, L. A. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.7 · Cited by 378
Recent advances in the neuropsychopharmacology of serotonergic hallucinogens
Halberstadt, A. L. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.016 · Cited by 312
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and p38 MAP kinase), Akt, and phospholipase D (dependent on the small G protein ADPribosylation factor-1 (ARF1)) (Kurrasch-Orbaugh et al., 2003a; González-Maeso et al., 2007; Schmid and Bohn, 2010; Barclay et al., 2011).”
BackgroundInfluential
Platelets and cancer: a casual or causal relationship: revisited
Menter, D. G., Tucker, S. C., Kopetz, S., Sood, A. K., Crissman, J. D., & Honn, K. V. (2014) · Cancer and Metastasis Reviews · doi:10.1007/s10555-014-9498-0 · Cited by 324
The neural basis of psychedelic action
Kwan, A. C., Olson, D. E., Preller, K. H., & Roth, B. L. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01177-4 · Cited by 330
Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways
López‐Giménez, J. F., & González‐Maeso, J. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_478 · Cited by 325
“For example, relative to 5-HT, some agonists, such as 3-trifluoromethylphenylpiperazine (TFMPP), preferentially activate the PLC-IP J.F. López-Giménez and J. González-Maeso pathway, whereas other agonists, such as LSD, showed a preference for the PLA2AA pathway.”
BackgroundInfluential
Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics.
de Vos, C. M. H., Mason, N. L., & Kuypers, K. P. C. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.724606 · Cited by 269
International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function
Barnes, N. M., Ahern, G. P., Bécamel, C., Bockaert, J., Camilleri, M., Chaumont‐Dubel, S., Claeysen, S., Cunningham, K. A., Fone, K. C. F., Gershon, M. D., et al. (2020) · Pharmacological Reviews · doi:10.1124/pr.118.015552 · Cited by 274
Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists
Moreno, J. L., Holloway, T. D., Albizu, L., Sealfon, S. C., & González‐Maeso, J. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.01.046 · Cited by 235
“However, some reports have implicated pertussis toxin-sensitive Gi/o proteins in the cel1lular responses mediated by 5-HT2AR activation [22,30].”
Background
Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo
Schmid, C. L., Raehal, K. M., & Bohn, L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708862105 · Cited by 231
Functions of 5-HT2A receptor and its antagonists in the cardiovascular system
Nagatomo, T., Rashid, M., Muntasir, H. A., & Komiyama, T. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.08.005 · Cited by 186
Serotonin, But Not N -Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo
Schmid, C. L., & Bohn, L. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1665-10.2010 · Cited by 181
“Diverse ligands to the 5-HT2AR have been shown to differentially activate downstream signaling cascades both in vitro and in vivo (Berg et al., 1998; Kurrasch-Orbaugh et al., 2003; González-Maeso et al., 2007; Schmid et al., 2008).”
Background
Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential
Seyedabadi, M., Ghahremani, M. H., & Albert, P. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.006 · Cited by 156
Lipid agonism: The PIP2 paradigm of ligand-gated ion channels
Hansen, S. B. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2015.01.011 · Cited by 146
“A third important class of lipases phospholipase A2 (PLA2) also exhibits GPCR regulation [103].”
Background
Biologic Functions of the G12 Subfamily of Heterotrimeric G Proteins: Growth, Migration, and Metastasis
Kelly, P., Casey, P. J., & Meigs, T. E. (2007) · Biochemistry · doi:10.1021/bi700235f · Cited by 137
Serotonergic signaling: multiple effectors and pleiotropic effects
Masson, J., Emerit, M. B., Hamon, M., & Darmon, M. C. (2012) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.50 · Cited by 132
Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity
Olson, D. E. (2022) · Biochemistry · doi:10.1021/acs.biochem.1c00812 · Cited by 146
How serotonin receptors regulate morphogenic signalling in neurons
Wirth, A., Holst, K., & Ponimaskin, E. G. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.03.007 · Cited by 125
NADPH oxidase in the vasculature: Expression, regulation and signalling pathways; role in normal cardiovascular physiology and its dysregulation in hypertension
Knock, G. A. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.09.029 · Cited by 110
TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension
Xia, Y., Fu, Z., Hu, J., Huang, C. Y., Paudel, O., Cai, S., Liedtke, W., & Sham, J. S. K. (2013) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00099.2013 · Cited by 108
On the analysis of ligand-directed signaling at G protein-coupled receptors
Ehlert, F. J. (2008) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-008-0260-4 · Cited by 94
“It has also been shown that several signaling proteins including isoforms of adenylate cyclase (Kurrasch-Orbaugh et al. 2003) and regulators of G protein signaling proteins (Neubig 2002) as well as proteins that interact with GPCRs (Bockaert et al.”
Background
Serotonin 2A Receptor (5-HT 2A R) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants
Duan, W., Cao, D., Wang, S., & Cheng, J. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00375 · Cited by 81
Role of Gq protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
Garcia, E. E., Smith, R. L., & Sanders‐Bush, E. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.03.013 · Cited by 78
“, G13 activation of PLD (McGrew et al., 2002;Kurrasch-Orbaugh et al., 2003) or Gi/o activation of the erg signaling pathway (Gonzales Maeso et al.”
Background
The role of phospholipases A2 in schizophrenia
Law, M. H., Cotton, R. G. H., & Berger, G. E. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001819 · Cited by 73
Serotonin 5‐HT2A receptor activation induces 2‐arachidonoylglycerol release through a phospholipase c‐dependent mechanism
Parrish, J. C., & Nichols, D. E. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04173.x · Cited by 63
Self-citation
Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase‐1, C/EBP‐β and ILAD‐1, a novel gene with homology to arrestins
Nichols, C. D., & Sanders‐Bush, E. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02515.x · Cited by 62
Regulation of Serotonin-Induced Trafficking and Migration of Eosinophils
Kang, B., Ha, S., Bahaie, N. S., Hosseinkhani, M., Ge, X.-N., Blumenthal, M., Rao, S. P., & Sriramarao, P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054840 · Cited by 56
“Additionally, in NIH3T3 fibroblasts transformed to stably express 5-HT2A, stimulation of 5-HT2A receptors has been shown to activate the PLA2 signaling pathways via G12/13 coupling [60].”
Background
PUFA and their derivatives in neurotransmission and synapses: a new hallmark of synaptopathies
Miceli, M. D., Bosch‐Bouju, C., & Layé, S. (2020) · Proceedings of The Nutrition Society · doi:10.1017/s0029665120000129 · Cited by 56
Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile
Holze, F., Singh, N., Liechti, M. E., & D’Souza, D. C. (2024) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2024.01.007 · Cited by 62
Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK
Daniele, S., Pozzo, E. D., Zappelli, E., & Martini, C. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.04.006 · Cited by 57
“Specifically, ERK1/2 activation and p38 pathway inhibition have been reported to involve agonistic effects at the 5HT 1A serotonin receptor [63,64], inhibition of the 5HT 2A serotonin receptor [63], and inhibition of SERT [65,66].”
Background
Serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways
Chattopadhyay, A. (2007) · CRC Press eBooks · doi:10.1201/9781420005752-11 · Cited by 56
The Effects of Hallucinogens on Gene Expression
Martin, D. A., & Nichols, C. D. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_479 · Cited by 51
“In mice lacking the Gaq protein, c-Fos induction following DOI is abolished, and the head-twitch response is markedly reduced (Garcia et al. 2007).”
BackgroundResultInfluential
Activation, internalization, and recycling of the serotonin 2A receptor by dopamine
Bhattacharyya, S., Raote, I., Bhattacharya, A., Miledi, R., & Panicker, M. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606578103 · Cited by 51
Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation
Wolf, G., Singh, S., Blakolmer, K., Lerer, L. B., Lifschytz, T., Heresco‐Levy, U., Lotan, A., & Lerer, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01832-z · Cited by 50
“Through stimulation of the 5-HT2A receptor, psychedelics activate intracellular signaling pathways such as PLC, PLA, and Src [138, 139].”
Background
Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action
Canal, C. E. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_107 · Cited by 49
“…arachidonic acid release (phospholipase A activation) do not reveal unique signaling properties of psychedelics, and like the phospholipase C-β-inositol phosphate pathway, many psychedelics are partial agonists relative to 5-HT (Kurrasch-Orbaugh et al. 2003a, b; Moya et al. 2007).”
Background
How much do we know about the coupling of G-proteins to serotonin receptors?
Giulietti, M., Vivenzio, V., Piva, F., Principato, G., Bellantuono, C., & Nardi, B. (2014) · Molecular Brain · doi:10.1186/s13041-014-0049-y · Cited by 46
“Gαi/o-?-? In mouse NIH3T3 cells cPLA2 (not PLC, IP3) (Kurrasch-Orbaugh, 2003) [52] Gα12/13-?-?”
Evaluating the dose-dependent mechanism of action of trazodone by estimation of occupancies for different brain neurotransmitter targets
Settimo, L., & Taylor, D. M. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881117742101 · Cited by 45
“…stress-related PERK/eIF2 α/ ATF4 pathway (Jiang et al., 2014) and also that 5-HT 2A agonism activates the mitogen-activated protein kinase p38 (Kurrasch-Orbaugh et al., 2003), it is evident that trazodone’s antagonist activity on the 5-HT 2A receptor is expected to decrease the activity of…”
Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD)
Govindula, A., Ranadive, N., Nampoothiri, M., Rao, C. M., Arora, D. S., & Mudgal, J. (2023) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-023-10064-z · Cited by 47
Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors
Blaazer, A. R., Smid, P., & Kruse, C. G. (2008) · ChemMedChem · doi:10.1002/cmdc.200800133 · Cited by 43
Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence
Boas, G. R. V., Lavorato, S. N., Paes, M. M., Galdino, P. M., Rescia, V. C., Cunha, M. S., de Magalhães-Filho, M. F., Ponsoni, L. F., de Carvalho, A. A. V., de Lacerda, R. B., et al. (2021) · Pharmaceuticals · doi:10.3390/ph14020148 · Cited by 42
“The “atypical” coupling represented by the blue circle demonstrates the activation of phospholipase A2 (PLA2) mediated by the 5-HT2A receptor and the subsequent release of arachidonic acid, described as a result of Gα12/13coupled, Rho-mediated, p38 activation in NIH 3T3 cells [48].”
Background
Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor
Gaitonde, S. A., Avet, C., Revenga, M. D. L. F., Blondel-Tepaz, É., Shahraki, A., Pastor, A. M., Talagayev, V., Robledo, P., Kolb, P., Selent, J., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02531-7 · Cited by 42
“Although earlier studies have implicated G α 12/ 13 in the activation of the phospholipase A 2 (PLA 2 ) pathway downstream of the 5-HT 2A R, other studies have also shown that there is no evidence for a direct coupling of these G proteins by the 5-HT 2A R [20, 43, 46].”
Background
Colocalisation of serotonin2A receptors with the glutamate receptor subunits NR1 and GluR2 in the dentate gyrus: An ultrastructural study of a modulatory role
Peddie, C. J., Davies, H. A., Colyer, F. M., Stewart, M. G., & Rodríguez, J. J. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.03.003 · Cited by 39
“5-HT2ARs also couple to phospholipase A2, generating the second messenger arachidonic acid, and can activate the ERK and p38 signalling cascades (Kurrasch-Orbaugh et al., 2003a,b; Parrish and Nichols, 2006).”
In vitro assays for the functional characterization of (psychedelic) substances at the serotonin receptor 5‐HT2AR
Pottie, E., & Stove, C. P. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15570 · Cited by 37
“Overall, biased agonism exerted by (psychedelic) agonists at the 5- HT2AR, as determined by in vitro functional assays, has mostly been discussed by comparison of outcomes in IP accumulation and AA release assays (Berg et al., 1998; Kurrasch- Orbaugh, Watts, et al., 2003; Marti- Solano et al., 2015; McLean, Parrish, e…”
BackgroundInfluential
Serotonin receptors 2A and 1A modulate anxiety-like behavior in post-traumatic stress disordered mice.
Xiang, M., Jiang, Y., Hu, Z., Yang, Y., Du, X., Botchway, B. O. A., & Fang, M. (2019) · PubMed Central · Cited by 36
Phosphorylation of JAK2 by serotonin 5-HT2A receptor activates both STAT3 and ERK1/2 pathways and increases growth of JEG-3 human placental choriocarcinoma cell
Oufkir, T., & Vaillancourt, C. (2011) · Placenta · doi:10.1016/j.placenta.2011.09.005 · Cited by 36
“One interesting pathway that we will explore in our follow-up study is that of phospholipase A2 (PLA2) which has been shown to be activated by the 5-HT2A-PKC-ERK1/2 axis [49,50].”
Background
Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate
Jiménez, J. H., & Bouso, J. C. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221104054 · Cited by 39
“Furthermore, PLA2 engagement requires a smaller receptor occupancy: binding to an estimated 3% of the receptors elicits the maximum response (Emax) versus a 7% occupancy for PLC-coupled 5-HT2A (Kurrasch-Orbaugh et al., 2003b).”
BackgroundInfluential
Hallucinogen actions on 5-HT receptors reveal distinct mechanisms of activation and signaling by G protein-coupled receptors
Weinstein, H. (2005) · The AAPS Journal · doi:10.1208/aapsj070485 · Cited by 34
5-HT2A and mGlu2/3 receptor interactions
Wischhof, L., & Koch, M. (2015) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000183 · Cited by 33
“Moreover, the two signaling pathways appear to have different receptor reserves in that activation of a much smaller fraction of the 5-HT2A receptor is required for the stimulation of the PLA2-mediated cascade versus PLC activation (Kurrasch-Orbaugh et al., 2003a, 2003b).”
Background
Serum calcium‐independent phospholipase A2 activity in bipolar affective disorder
Ross, B. M., Hughes, B., Kish, S. J., & Warsh, J. J. (2006) · Bipolar Disorders · doi:10.1111/j.1399-5618.2006.00299.x · Cited by 33
The renaissance in psychedelic research: What do preclinical models have to offer
Murnane, K. S. (2018) · Progress in brain research · doi:10.1016/bs.pbr.2018.08.003 · Cited by 35
The crosstalk between 5-HT2AR and mGluR2 in schizophrenia
Saha, S., & González‐Maeso, J. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109489 · Cited by 30
Benzydamine—An Affordable Over-the-Counter Drug with Psychoactive Properties—From Chemical Structure to Possible Pharmacological Properties
Ősz, B.-E., Jîtcă, G., Sălcudean, A., Rusz, C.-M., & Vari, C.-E. (2023) · Pharmaceuticals · doi:10.3390/ph16040566 · Cited by 32
The evolution of N, N-Dimethyltryptamine: from metabolic pathways to brain connectivity
Gupta, S., Bhatnagar, R. K., Gupta, D., Maharaj Kumari, K., & Chopra, A. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06777-z · Cited by 32
Cytosolic phospholipase A2: a member of the signalling pathway of a new G protein α subunit in Sporothrix schenckii
Valentín-Berríos, S., González-Velázquez, W., Pérez-Sánchez, L., Gonzalez-Mendez, R. R., & Valle, N. R.-D. (2009) · BMC Microbiology · doi:10.1186/1471-2180-9-100 · Cited by 30
“In higher eukaryotes, members of the Gα class are known to regulate adenylate cyclase [20], cGMP phosphodiesterase [21], phosphoinositide-3-kinase [22], calcium and potassium channels [22-24], and the activity of phospholipases [9,25-28].”
Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice
Retamal, J. S., Grace, M. S., Dill, L. K., Ramírez-García, P. D., Peng, S., Gondin, A. B., Bennetts, F. M., Alvi, S., Rajasekhar, P., Almazi, J. G., et al. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00593-7 · Cited by 28
Serotonin and chronic hypoxic pulmonary hypertension activate a NADPH oxidase 4 and TRPM2 dependent pathway for pulmonary arterial smooth muscle cell proliferation and migration
Song, J.-L., Zheng, S., He, R., Gui, L., Lin, M., & Sham, J. S. K. (2021) · Vascular Pharmacology · doi:10.1016/j.vph.2021.106860 · Cited by 27
TCB-2 [(7R)-3-bromo-2, 5-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine]: A hallucinogenic drug, a selective 5-HT2A receptor pharmacological tool, or none of the above?
Giovanni, G. D., & Deurwaerdère, P. D. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.10.004 · Cited by 25
“Nonetheless, this phenomenon would not account for their psychogenic effects; lisuride has a profile similar to DOB in this regard (Kurrasch-Orbaugh et al., 2003b).”
D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats
Bhattacharjee, A. K., Chang, L., White, L., Bazinet, R. P., & Rapoport, S. I. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600290 · Cited by 25
Role of a small G protein Ras in cellular immune response of the beet armyworm, Spodoptera exigua
Lee, S., Shrestha, S. S., Surakasi, V. P., & Kim, Y. (2010) · Journal of Insect Physiology · doi:10.1016/j.jinsphys.2010.12.003 · Cited by 25
Serotonergic Suppression of Mouse Prefrontal Circuits Implicated in Task Attention
Tian, M. K., Schmidt, E. F., & Lambe, E. K. (2016) · eNeuro · doi:10.1523/eneuro.0269-16.2016 · Cited by 26
“, 2010; Weber and Andrade, 2010; Avesar and Gulledge, 2012), although previous work has demonstrated the capacity of serotonin and 5-HT2A agonists to exert direct inhibitory effects through 5-HT2A receptors or heteromers (Carr et al., 2002; Kurrasch-Orbaugh et al., 2003; GonzálezMaeso et al., 2007; Moreno et al., 2011…”
Background
Chronic fluoxetine upregulates arachidonic acid incorporation into the brain of unanesthetized rats
Qu, Y., Chang, L., Klaff, J., Seemann, R., GREENSTEIN, D. K., & Rapoport, S. I. (2006) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.01.008 · Cited by 23
5-HT activates ERK MAP kinase in cultured-human peripheral blood mononuclear cells via 5-HT1A receptors
Cloëz-Tayarani, I., Kayyali, U. S., Fanburg, B. L., & Cavaillon, J. (2004) · Life Sciences · doi:10.1016/j.lfs.2004.09.006 · Cited by 21
The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies
Low, Z. X. B., Ng, W. S., Lim, E. S. Y., Goh, B. H., & Kumari, Y. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111139 · Cited by 22
Psychedelics action and schizophrenia
Maćkowiak, M. (2023) · Pharmacological Reports · doi:10.1007/s43440-023-00546-5 · Cited by 22
“Activation of the 5-HT 2A receptor also induces G i/o -dependent Gβγ -associates stimulation of extracellular signal-regulated kinase, p44/p42 (ERK1/2) [17].”
Background
5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail
Barclay, Z., Dickson, L., Robertson, D. N., Johnson, M. S., Holland, P. J., Rosie, R., Sun, L., Fleetwood‐Walker, S., Lutz, E. M., & Mitchell, R. (2011) · Biochemical Journal · doi:10.1042/bj20101844 · Cited by 20
The Gq and G12 Families of Heterotrimeric G Proteins Report Functional Selectivity
Zhang, L., Brass, L. F., & Manning, D. R. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.050906 · Cited by 18
“A great deal of information regarding selectivity has been gained through studies of receptors for serotonin (Berg et al., 1998, 2001; Kurrasch-Orbaugh et al., 2003; De Deurwaerdère et al., 2004), dopamine (Lawler et al., 1999; Kilts et al., 2002; Mottola et al., 2002; Gay et al., 2004;…”
Background
Allosteric Modulation of the M3 Muscarinic Receptor by Amiodarone and N-Ethylamiodarone: Application of the Four-Ligand Allosteric Two-State Model
Stahl, E. L., Elmslie, G., & Ellis, J. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.072991 · Cited by 18
“Kurrasch-Orbaugh et al. (2003a) found that different 5HT2A receptor agonists possessed opposite functional selectivity for the two responses in NIH-3T3 cells; indeed, these authors also found different magnitudes of receptor reserve for the two responses.”
Background
An Overview on the Hallucinogenic Peyote and Its Alkaloid Mescaline: The Importance of Context, Ceremony and Culture
Kleffens, M. D.-V., Zimmermann-Klemd, A. M., & Gründemann, C. (2023) · Molecules · doi:10.3390/molecules28247942 · Cited by 20
Ligand bias and inverse agonism on 5‐HT2A receptor‐mediated modulation of G protein activity in post‐mortem human brain
Arrate, I. M., Miranda-Azpiazu, P., Horrillo, I., Dı́ez-Alarcia, R., & Meana, J. J. (2024) · British Journal of Pharmacology · doi:10.1111/bph.16368 · Cited by 19
Hippocampal Neurogenesis
Catlow, B. J., Jalloh, A., & Sanchez‐Ramos, J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800212-4.00077-7 · Cited by 18
Natural Psychoplastogens As Antidepressant Agents
Benko, J., & Vranková, S. (2020) · Molecules · doi:10.3390/molecules25051172 · Cited by 17
“Increased [Ca2+] leads to activation of the cascade, including protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and cAMP response-element binding protein (CREB).”
BackgroundInfluential
Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence
McNamara, R. K., Szeszko, P. R., Smesny, S., Ikuta, T., DeRosse, P., Vaz, F. M., Milleit, B., Hipler, U., Wiegand, C., Hesse, J., et al. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.12.007 · Cited by 16
“…case of membrane damage, the activity of cPLA2 and iPLA2 (as inPLA2 sum activity) in turn is increased by interaction with extracellular secretory non-pancreatic, and calcium-dependent PLA2 isoenzymes (Garcia and Kim, 1997; Balsinde et al., 1998; Kuwata et al., 2000; Kurrasch-Orbaugh et al., 2003).”
Background
The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo
Murnane, K. S., Güner, O. F., Bowen, J. P., Rambacher, K. M., Moniri, N. H., Murphy, T. J., Daphney, C. M., Oppong‐Damoah, A., & Rice, K. C. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.04.003 · Cited by 16
Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation
Santini, M. A., Klein, A. B., El-Sayed, M., Ratner, C., Knudsen, G. M., Mikkelsen, J. D., & Aznar, S. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.05.048 · Cited by 15
5-Oxo-ETE regulates tone of guinea pig airway smooth muscle via activation of Ca2+pools and Rho-kinase pathway
Mercier, F., Morin, C., Cloutier, M., Proteau, S., Rokach, J., Powell, W. S., & Rousseau, É. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00005.2004 · Cited by 15
“In addition to its involvement in Ca(2) sensitization, the Rho-kinase pathway has also been shown to be involved in agonist-induced stimulation of arachidonic acid release from fibroblasts, presumably mediated by activation of cPLA2 (18).”
Background
Serotonin Modulation of Dorsoventral Hippocampus in Physiology and Schizophrenia
Kandilakis, C. L., & Papatheodoropoulos, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157253 · Cited by 14
Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology
Jastrzębski, M. K., Wójcik, P., Grudzińska, A., Andreozzi, G., Vetrò, T., Asim, A., Mudgal, A., Czapiński, J., Wróbel, T. M., Bartuzi, D., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.002 · Cited by 15
“Phospholipase A2 is activated through interactions between 5-HT 2A and G 12/13 proteins 29 , while phospholipase D directly binds to both 5-HT 2A receptors and ADP-ribosylation factor (Arf) 30 .”
Novel Bivalent 5-HT2AReceptor Antagonists Exhibit High Affinity and Potencyin Vitroand Efficacyin Vivo
Soto, C. A., Shashack, M. J., Fox, R. G., Bubar, M. J., Rice, K. C., Watson, C. S., Cunningham, K. A., Gilbertson, S. R., & Anastasio, N. C. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00309 · Cited by 13
His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics
Martín‐Guerrero, S. M., Alonso-Batan, P., Iglesias, A., Cimadevila, M., Brea, J. M., Loza, M. I., Casado, P., Martín‐Oliva, D., Cutillas, P. R., González‐Maeso, J., et al. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114440 · Cited by 13
In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease
Bhattacharjee, A. K., Meister, L. M., Chang, L., Bazinet, R. P., White, L., & Rapoport, S. I. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.06.012 · Cited by 13
“These receptors, like D2-receptors, can be coupled to cPLA2 to release AA from membrane phospholipid (Berg et al., 1998; Garcia and Kim, 1997; Kurrasch-Orbaugh et al., 2003; Qu et al., 2003).”
Background
Angiotensin II stimulates fibronectin protein synthesis via a Gβγ/arachidonic acid-dependent pathway
Alexander, L. D., Ding, Y., Alagarsamy, S., & Cui, X.-L. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00094.2014 · Cited by 12
Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder
Alexander, C., & Vasefi, M. (2021) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2021.08.001 · Cited by 12
“…et al., 2020; Avery et al., 2014; Cheng et al., 2003, 2006; Dong et al., 2001; Helmstetter (1992); Helmstetter and Bellgowan, 1993; Knight et al., 2005; LaBar et al., 1998; Maren (2001); Ono et al., 1985; Pitkänen et al., 1997; Veening et al., 1984; Weller and Smith, 1982; Wilensky et al., 2006).”
Selectivity for G Protein or Arrestin-Mediated Signaling
Bohn, L. (2009) · The Receptors · doi:10.1007/978-1-60327-335-0_5 · Cited by 11
Serotonin 2C receptors are also important in head-twitch responses in male mice
Custodio, R. J. P., Ortiz, D. M., Lee, H. J., Sayson, L. V., Buctot, D., Kim, M., Lee, Y. S., Cheong, J. H., Cheong, J. H., & Kim, H. J. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06482-9 · Cited by 16
Serotonin 2A receptors and cannabinoids
Ibarra‐Lecue, I., Dı́ez-Alarcia, R., & Urigüen, L. (2021) · Progress in brain research · doi:10.1016/bs.pbr.2021.01.004 · Cited by 11
Serotonin 2A (5-HT2A) receptor as evolving biological target: function, structure, ligands and role in the therapy of neuropsychiatric diseases
Fryc, M., Kluzik, D., Czopek, A., Jończyk, J., & Zagórska, A. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110622 · Cited by 10
Mesenchymal stem cells and their conditioned medium as potential therapeutic strategies in managing comorbid anxiety in rat sepsis induced by cecal ligation and puncture.
Ranjbaran, M., Kianian, F., Kadkhodaee, M., Seifi, B., Ashabi, G., Akhondzadeh, F., Adelipour, M., Izad, M. H., & Abdolmohammadi, K. (2022) · PubMed Central · doi:10.22038/ijbms.2022.61860.13690 · Cited by 9
“Reductions in the expression of 5-HT2A receptors and phosphorylation of ERK1/2 and an increase in the expression of 5-HT1A receptors in the hippocampal tissue samples were observed in the MSC and CM groups.”
Influential
Are we hallucinating or can psychedelic drugs modulate the immune system to control inflammation?
Qureshi, O., Cowley, J., Pegg, A., Cooper, A. J., Gordon, J., Brady, C., Belli, A., Butterworth, S., Upthegrove, R., Andrews, N., et al. (2025) · British Journal of Pharmacology · doi:10.1111/bph.70138 · Cited by 11
Cane Toad Skin Extract—Induced Upregulation and Increased Interaction of Serotonin 2A and D2 Receptors via Gq/11 Signaling Pathway in CLU213 Cells
Zulfiker, A., Hashimi, S., Good, D., Grice, I., & Wei, M. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25627 · Cited by 8
“Agonists working on 5-HT2AR may stimulate several signal transduction pathways, such as activation of MAPK, PLC-b, and PLA2 [Kurrasch-Orbaugh et al., 2003] leading to longterm transcriptional changes.”
Background
Tryptamines as Ligands and Modulators of the Serotonin 5‑HT2A Receptor and the Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens
Jensen, N. (2005) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-2111 · Cited by 9
Biased Signaling in Psychedelic Action
Wacker, D., & McCorvy, J. D. (2025) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-062124-012545 · Cited by 9
Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice
Kim, Y., Jeon, S. J., Gonzales, E. L., Shin, D., Remonde, C. G., Ahn, T., & Shin, C. Y. (2022) · Scientific Reports · doi:10.1038/s41598-022-25582-8 · Cited by 7
Psychedelics and Hallucinogens in Psychiatry: Finding New Pharmacological Targets
de Sousa, T. R., Rema, J., Machado, S. E. D. C., & Novais, F. (2021) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026621666211201145800 · Cited by 7
An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)2Areceptors in rat cortex: Blockade by clozapine and mirtazapine
la Cour, C. M., Chaput, C., Touzard, M., & Millan, M. J. (2008) · Synapse · doi:10.1002/syn.20587 · Cited by 7
Exploring factors associated with the intensity of a mystical experience following naturalistic psychedelic use: A retrospective survey
Roméo, B., Kervadec, E., Fauvel, B., Strika-Bruneau, L., Amirouche, A., Verroust, V., Piolino, P., & Benyamina, A. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111300 · Cited by 7

Authors: Kurrasch‐Orbaugh, D. M., Parrish, J. C., Watts, V. J., & Nichols, D. E.
Affiliations: Purdue University West Lafayette (US)
ORCID: Watts, Val J.
Nichols, David E.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2003-07-21
Volume: 86
Issue: 4
Pages: 980-991
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1046/j.1471-4159.2003.01921.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks