5-HT2A receptor

The 5-HT_2A receptor is a subtype of the 5-HT₂ receptor which belongs to the serotonin receptor family and is a G protein coupled receptor. Activation of this receptor has a generally excitatory effect on most regions of the brain, although it may also have an inhibitory effect on certain areas such as the visual cortex.

History

Serotonin receptors were split into two classes when it was discovered that some of the serotonin induced changes in the gut could be blocked by morphine, whilst the remainder of the response was inhibited by dibenzyline, leading to the naming of M and D receptors respectively. Using a radioligand approach, spiperone and LSD were shown to label two different serotonin receptors, and neither of them displaced morphine, leading to naming of the 5-HT1 5-HT2 and 5-HT3 receptors, corrisponding to high affinity sites from LSD, spiperone and morphine respectively. Later it was shown that the 5-HT2 receptor was actually two seperate molecular entities, the 5-HT2A (which reflects most 5-HT2 mediated effects) and the 5-HT2B receptor. (See Hoyer et al., Pharmacology Biochemistry and Behavior, Volume 71, Issue 4 , April 2002, Pages 533-554)

Signalling Cascade

As the 5-HT_2A receptor is G-protein linked, the first step in its signalling cascade, after it is stimulated by an agonist, is activation of its associated G-protein. The 5-HT_2A receptor has been shown to be linked to most major G-protein systems, but classically it linked to the G_q G-protein. Activation of this receptor stimulates phospholipase C (PLC) activity, which subsequently promotes the release of DAG and IP3, which in turn stimulate PKC activity and Ca²⁺ release.

Pharmacology

The 5-HT_2A receptor mediates the effects of the "classic" hallucinogens like LSD, psilocin, and mescaline, which act as partial agonists at this receptor. Inhibition of firing of neurons in the visual cortex, that are normally involved in the perception of the edges of objects, is thought to be involved in the characteristic visual hallucinations produced by these drugs.

APD125, a new sleeping pill recently developed by Arena Pharmaceuticals and currently in Phase 2 trials, acts as a selective 5-HT_2A antagonist. Other drugs that affect this receptor include the atypical antipsychotic drug risperidone, which acts as 5-HT_2A antagonist, in addition to its primary effects as a dopamine antagonist.

Additional references

1. D.M. Kurrasch-Orbaugh (2003). "A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases". J. Neurochem. 86 (4): 980–91. PMID 12887695.
2. D.M. Kurrasch-Orbaugh (2003). "Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves". J. Pharmacol. Exp. Ther. 304 (1): 229–37. PMID 12490596.
3. J.J. Chambers (2002). "A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor". J. Comput. Aided Mol. Des. 16 (7): 511–20. PMID 12510883.

External links

• IUPHAR GPCR Database - 5-HT_2A
• A picture of the protein