{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:56:09Z","timestamp":1791039369277,"version":"4.1.0"},"reference-count":49,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,6,15]]},"abstract":"<jats:p>The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD (phospholipase D), which appears to be achieved through a mechanism independent of heterotrimeric G-proteins. In the present study we show that wild-type and inactive constructs of PLD1 (but not PLD2) respectively facilitate and inhibit ARF-dependent PLD signalling by the 5-HT2AR. Furthermore we demonstrate that PLD1 specifically co-immunoprecipitates with the receptor and binds to a distal site in GST (glutathione transferase) fusion protein constructs of its C-terminal tail which is distinct from the ARF-interaction site, thereby suggesting the existence of a functional ARF\u2013PLD signalling complex directly associated with this receptor. This reveals the spatial co-ordination of an important GPCR, transducer and effector into a physical complex that is likely to reinforce the impact of receptor activation on a heterotrimeric G-protein-independent signalling pathway. Signalling of this receptor through such non-canonical pathways may be important to its role in particular disorders.<\/jats:p>","DOI":"10.1042\/bj20101844","type":"journal-article","created":{"date-parts":[[2011,3,17]],"date-time":"2011-03-17T12:03:08Z","timestamp":1300363388000},"page":"651-660","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail"],"prefix":"10.1042","volume":"436","author":[{"given":"Zo\u00eb","family":"Barclay","sequence":"first","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Dickson","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek\u00a0N.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie\u00a0S.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela\u00a0J.","family":"Holland","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Rosie","sequence":"additional","affiliation":[{"name":"Centre for Neuroregeneration, School of Biomedical Sciences, Chancellor's Building, University of Edinburgh, Edinburgh EH16 4SB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Sun","sequence":"additional","affiliation":[{"name":"Centre for Neuroregeneration, School of Biomedical Sciences, Chancellor's Building, University of Edinburgh, Edinburgh EH16 4SB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Fleetwood-Walker","sequence":"additional","affiliation":[{"name":"Centre for Neuroregeneration, School of Biomedical Sciences, Chancellor's Building, University of Edinburgh, Edinburgh EH16 4SB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve\u00a0M.","family":"Lutz","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1XW, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh EH8 9XD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2011,5,27]]},"reference":[{"key":"2021112215194177400_B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1471-4159.2003.01693.x","article-title":"The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice","volume":"85","author":"Dean","year":"2003","journal-title":"J. Neurochem."},{"key":"2021112215194177400_B2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0031-6997(25)06783-3","article-title":"International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin)","volume":"46","author":"Hoyer","year":"1994","journal-title":"Pharmacol. Rev."},{"key":"2021112215194177400_B3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0163-7258(98)00019-9","article-title":"5-Hydroxytryptamine2- family receptors (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where structure meets function","volume":"79","author":"Roth","year":"1998","journal-title":"Pharmacol. Ther."},{"key":"2021112215194177400_B4","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.neuron.2007.01.008","article-title":"Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior","volume":"53","author":"Gonzalez-Maeso","year":"2007","journal-title":"Neuron"},{"key":"2021112215194177400_B5","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/S0022-3565(24)35225-5","article-title":"Mechanisms of 5-hydroxytryptamine(2A) receptor activation of the mitogen-activated protein kinase pathway in vascular smooth muscle","volume":"291","author":"Banes","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112215194177400_B6","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1124\/jpet.102.038083","article-title":"Activation of extracellular-regulated kinase by 5-hydroxytryptamine(2A) receptors in PC12 cells is protein kinase C-independent and requires calmodulin and tyrosine kinases","volume":"303","author":"Quinn","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112215194177400_B7","doi-asserted-by":"crossref","first-page":"21004","DOI":"10.1074\/jbc.M512096200","article-title":"5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factor-\u03b1-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells","volume":"281","author":"Gooz","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B8","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1073\/pnas.0708862105","article-title":"Agonist-directed signaling of the serotonin 2A receptor depends on \u03b2-arrestin-2 interactions in vivo","volume":"105","author":"Schmid","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215194177400_B9","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1124\/mol.54.1.94","article-title":"Effector pathway-dependent relative efficacy at serotonin type\u00a02A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus","volume":"54","author":"Berg","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"2021112215194177400_B10","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1046\/j.1471-4159.2003.01921.x","article-title":"A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases","volume":"86","author":"Kurrasch-Orbaugh","year":"2003","journal-title":"J. Neurochem."},{"key":"2021112215194177400_B11","doi-asserted-by":"crossref","first-page":"14825","DOI":"10.1074\/jbc.272.23.14825","article-title":"Identification and localization of a skeletal muscle serotonin 5-HT2A receptor coupled to the Jak\/STAT pathway","volume":"272","author":"Guillet-Deniau","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B12","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1471-4159.2004.02832.x","article-title":"Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells","volume":"92","author":"Johnson-Farley","year":"2005","journal-title":"J. Neurochem."},{"key":"2021112215194177400_B13","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1523\/JNEUROSCI.1090-09.2009","article-title":"PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors","volume":"29","author":"Abbas","year":"2009","journal-title":"J. Neurosci."},{"key":"2021112215194177400_B14","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/32937","article-title":"Rhodopsin-family receptors associate with small G proteins to activate phospholipase D","volume":"392","author":"Mitchell","year":"1998","journal-title":"Nature"},{"key":"2021112215194177400_B15","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1124\/mol.64.5.1239","article-title":"Selective interaction of ARF1 with the carboxy-terminal tail domain of the 5-HT2A receptor","volume":"64","author":"Robertson","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"2021112215194177400_B16","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.cellsig.2006.02.002","article-title":"Role of the conserved NPxxY motif of the 5-HT2A receptor in determining selective interaction with isoforms of ADP-ribosylation factor (ARF)","volume":"18","author":"Johnson","year":"2006","journal-title":"Cell. Signalling"},{"key":"2021112215194177400_B17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1124\/jpet.102.042184","article-title":"Serotonin 5- hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves","volume":"304","author":"Kurrasch-Orbaugh","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112215194177400_B18","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1124\/jpet.106.117507","article-title":"Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5- HT)2A and 5-HT2C receptors","volume":"321","author":"Moya","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112215194177400_B19","doi-asserted-by":"crossref","first-page":"13157","DOI":"10.1074\/jbc.273.21.13157","article-title":"ADP-ribosylation factor and Rho proteins mediate fMLP-dependent activation of phospholipase D in human neutrophils","volume":"273","author":"Fensome","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B20","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1210\/endo.141.6.7517","article-title":"The activation of phospholipase D by endothelin-1, angiotensin II, and platelet-derived growth factor in vascular smooth muscle A10 cells is mediated by small G proteins of the ADP-ribosylation factor family","volume":"141","author":"Shome","year":"2000","journal-title":"Endocrinology"},{"key":"2021112215194177400_B21","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1124\/mol.59.6.1523","article-title":"ADP-ribosylation factor-dependent phospholipase D activation by VPAC receptors and a PAC(1) receptor splice variant","volume":"59","author":"McCulloch","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"2021112215194177400_B22","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S0166-2236(00)01643-X","article-title":"G-protein-independent signaling by G-protein-coupled receptors","volume":"23","author":"Heuss","year":"2000","journal-title":"Trends Neurosci."},{"key":"2021112215194177400_B23","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1172\/JCI26950","article-title":"When 7 transmembrane receptors are not G protein-coupled receptors","volume":"115","author":"Rajagopal","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021112215194177400_B24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1039\/b706343a","article-title":"When a G protein-coupled receptor does not couple to a G protein","volume":"3","author":"Sun","year":"2007","journal-title":"Mol. Biosyst."},{"key":"2021112215194177400_B25","doi-asserted-by":"crossref","first-page":"9979","DOI":"10.1074\/jbc.M206709200","article-title":"ADP- ribosylation factor-dependent phospholipase D2 activation is required for agonist-induced mu-opioid receptor endocytosis","volume":"278","author":"Koch","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B26","doi-asserted-by":"crossref","first-page":"8752","DOI":"10.1523\/JNEUROSCI.3155-04.2004","article-title":"Ral and phospholipase D2-dependent pathway for constitutive metabotropic glutamate receptor endocytosis","volume":"24","author":"Bhattacharya","year":"2004","journal-title":"J. Neurosci."},{"key":"2021112215194177400_B27","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1091\/mbc.11.12.4359","article-title":"Dual requirement for rho and protein kinase C in direct activation of phospholipase D1 through G protein-coupled receptor signaling","volume":"11","author":"Du","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"2021112215194177400_B28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1074\/jbc.275.1.71","article-title":"Inhibition of subsets of G protein-coupled receptors by empty mutants of G protein \u03b1 subunits in Go, G11, and G16","volume":"275","author":"Yu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0028-3908(97)00024-5","article-title":"Ontogenetic and pharmacological studies on metabotropic glutamate receptors coupled to phospholipase D activation","volume":"36","author":"Klein","year":"1997","journal-title":"Neuropharmacology"},{"key":"2021112215194177400_B30","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/274904a0","article-title":"Is GABA release modulated by presynaptic receptors?","volume":"274","author":"Mitchell","year":"1978","journal-title":"Nature"},{"key":"2021112215194177400_B31","doi-asserted-by":"crossref","first-page":"33818","DOI":"10.1074\/jbc.M305825200","article-title":"ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor","volume":"278","author":"Mitchell","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B32","doi-asserted-by":"crossref","first-page":"223\u2013229","DOI":"10.1016\/j.pep.2008.08.003","article-title":"One-step isolation of plasma membrane proteins using magnetic beads with immobilized concanavalin A","volume":"62","author":"Lee","year":"2008","journal-title":"Protein Expr. Purif."},{"key":"2021112215194177400_B33","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/0006-8993(95)00865-N","article-title":"DOI, a 5-HT2A\/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum","volume":"698","author":"Ichikawa","year":"1995","journal-title":"Brain Res."},{"key":"2021112215194177400_B34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/sj.npp.1300819","article-title":"Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex","volume":"31","author":"Pehek","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"2021112215194177400_B35","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nchembio.140","article-title":"Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness","volume":"5","author":"Scott","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"2021112215194177400_B36","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1016\/j.bmcl.2009.02.125","article-title":"Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity","volume":"19","author":"Lavieri","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2021112215194177400_B37","doi-asserted-by":"crossref","first-page":"667\u2013675","DOI":"10.1111\/j.1432-1033.1994.00667.x","article-title":"Mechanisms of phospholipase D stimulation by m3 muscarinic acetylcholine receptors. Evidence for involvement of tyrosine phosphorylation","volume":"225","author":"Schmidt","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"2021112215194177400_B38","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1074\/jbc.271.2.695","article-title":"Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and Fyn-dependent T cell activation","volume":"271","author":"Hanke","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B39","doi-asserted-by":"crossref","first-page":"7084","DOI":"10.1021\/bi0100586","article-title":"Structural determinants for potent, selective dual site inhibition of human pp60c-src by 4-anilinoquinazolines","volume":"40","author":"Tian","year":"2001","journal-title":"Biochemistry"},{"key":"2021112215194177400_B40","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1074\/jbc.272.6.3860","article-title":"Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-\u03b1","volume":"272","author":"Hammond","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B41","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1124\/mol.107.041780","article-title":"Small molecule disruption of G-protein \u03b2\u03b3 subunit signaling inhibits neutrophil chemotaxis and inflammation","volume":"73","author":"Lehmann","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"2021112215194177400_B42","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1083\/jcb.200302033","article-title":"Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs","volume":"162","author":"Du","year":"2003","journal-title":"J. Cell Biol."},{"key":"2021112215194177400_B43","doi-asserted-by":"crossref","first-page":"21746","DOI":"10.1074\/jbc.M702968200","article-title":"Phospholipase D1 production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granules at a late stage","volume":"282","author":"Zeniou-Meyer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021112215194177400_B44","doi-asserted-by":"crossref","first-page":"1024\u20131030","DOI":"10.1091\/mbc.e03-09-0673","article-title":"Phospholipase D2 localizes to the plasma membrane and regulates angiotensin II receptor endocytosis","volume":"15","author":"Du","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"2021112215194177400_B45","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.cellsig.2009.07.014","article-title":"ADP-ribosylation factor 6 regulates mu-opioid receptor trafficking and signaling via activation of phospholipase D2","volume":"21","author":"Rankovic","year":"2009","journal-title":"Cell. Signalling"},{"key":"2021112215194177400_B46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0163-7258(02)00170-5","article-title":"Pharmacological importance of phospholipase D and phosphatidic acid in the regulation of the mitogen-activated protein kinase cascade","volume":"94","author":"Rizzo","year":"2002","journal-title":"Pharmacol. Ther."},{"key":"2021112215194177400_B47","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1210\/me.2008-0436","article-title":"Role of phospholipase D in parathyroid hormone type\u00a01 receptor signaling and trafficking","volume":"23","author":"Garrido","year":"2009","journal-title":"Mol. Endocrinol."},{"key":"2021112215194177400_B48","first-page":"1429\u20131442","article-title":"The differential regulation of phosphatidylinositol 4-phosphate 5-kinases and phospholipase D1 by ADP-ribosylation factors 1 and 6","volume":"1761","author":"Perez-Mansilla","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112215194177400_B49","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.bbalip.2009.03.007","article-title":"Phosphatidic acid regulation of phosphatidylinositol 4-phosphate 5- kinases","volume":"1791","author":"Cockcroft","year":"2009","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/436\/3\/651\/668607\/bj4360651.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/436\/3\/651\/668607\/bj4360651.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T15:52:38Z","timestamp":1741103558000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/436\/3\/651\/45746\/5-HT2A-receptor-signalling-through-phospholipase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,27]]},"references-count":49,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2011,6,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20101844","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,27]]}}}