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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

Biochemical Journal June 15, 2011 DOI: 10.1042/bj20101844 (opens in new tab)

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AI-extracted from the abstract
Characteristics Basic science laboratory study Peer reviewed
Topics Serotonin
Key points The authors report that PLD1, but not PLD2, facilitates and inhibits ARF-dependent PLD signalling by the 5-HT2A receptor, and that PLD1 co-immunoprecipitates with the receptor and binds a distal site on its C-terminal tail distinct from the ARF-interaction site. They propose that this reflects a functional ARF-PLD signalling complex directly associated with the receptor.

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.

Comparable studies

Other experimental studies on serotonin, most cited first.

Study Year Design Participants
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers 1998 Experimental study
Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin 2000 Experimental study
Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain 1988 Experimental study
The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... 1992 Laboratory study
5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain 1997 Experimental study

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