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5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail

Barclay, Zoë and Dickson, Louise and Robertson, Derek N and Johnson, Melanie S and Holland, Pamela J and Rosie, Roberta and Sun, Liting and Fleetwood-Walker, Sue and Lutz, Eve M and Mitchell, Rory (2011) 5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail. Biochemical Journal, 436 (3). pp. 651-60.

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Abstract

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-PLD 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.

Author(s):Barclay, Zoë, Dickson, Louise, Robertson, Derek N, Johnson, Melanie S, Holland, Pamela J, Rosie, Roberta, Sun, Liting, Fleetwood-Walker, Sue, Lutz, Eve M and Mitchell, Rory
Item type:Article
ID code:32770
Keywords:ribosylation factors, amino acid sequence, animals, cos cells, cercopithecus aethiops, phospholipase D, receptor , signal transduction, serotonin, Therapeutics. Pharmacology, Engineering design, Biochemistry, Cell Biology, Molecular Biology
Subjects:Medicine > Therapeutics. Pharmacology
Technology > Engineering (General). Civil engineering (General) > Engineering design
Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Pure Administrator
Date deposited:24 Aug 2011 09:14
Last modified:22 Mar 2019 03:23
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URI:https://strathprints.strath.ac.uk/id/eprint/32770
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