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

Zoë Barclay, Louise Dickson, Derek N Robertson, Melanie S Johnson, Pamela J Holland, Roberta Rosie, Liting Sun, Sue Fleetwood-Walker, Eve M Lutz, Rory Mitchell

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15 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)651-60
Number of pages10
JournalBiochemical Journal
Issue number3
Publication statusPublished - 2011


  • ribosylation factors
  • amino acid sequence
  • animals
  • cos cells
  • cercopithecus aethiops
  • phospholipase D
  • receptor
  • signal transduction
  • serotonin


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