5-HT2A receptor

The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor which belongs to the serotonin receptor family and is a G protein coupled receptor(GPCR). This is the main excitatory receptor subtype among the GPCRs for serotonin(5-HT), although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex. This receptor was given importance first as the target of psychedelic drugs like LSD. Later it came back to prominence bacause it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones. 5-HT2A also happens to be a necessary receptor for clathrin mediated endocytosis of the human polyoma virus called JC virus, the causative agent of progressive multifocal leukoencephalopathy (PML), that enters cells like oligodendrocytes, astrocytes, B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked sialic acid component of the JCV receptor and the 5HT2A receptor in order to endocytose JCV.

History
Serotonin receptors were split into two classes by Gaddum and Picarelli 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. 5-HT2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by by Gaddum and Picarelli. In the pre-molecular-clong era when radioligand binding and displacement was the only major tool, 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, corresponding to high affinity sites from LSD, spiperone and morphine respectively (?). Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, renaming the 5-HT2 into 5-HT2A. Thus the 5-HT2 receptor family comprizes of three separate molecular entities, the 5-HT2A (erstwhile 5HT2 or D), the 5-HT2B (erstwhile 5-HT2F) and the 5HT2C (erstwhile 5-HT1C) receptors.

Distribution
5-HT2A is expressed both inside and outside the nervous system. In the CNS it is expressed near most of the serotoninergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and olfactory tubercle. Outside the CNS it is highly expressed in platelets and some smooth muscles.

Signalling Cascade
As the 5-HT2A 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-HT2A receptor has been shown to be linked to most major G-protein systems, but classically it linked to the Gq G-protein. Activation of this receptor stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca2+ release.

Agonists
The 5-HT2A receptor mediates the effects of the "classic" hallucinogens like LSD, psilocin, and mescaline, which act as full or 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.

Antagonists
Though Ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as metergoline bind preferentially to members of the 5-HT2 receptor family. A number of antagonists for 5-HT2A/2C are currently available but none are absolutely specific for 2A. Ketanserin, the prototypic 5-HT2A receptor antagonist potently blocks 5-HT2A receptors, less potently blocks 5-HT2C receptors, and has no significant effect on 5-HT3 or 5-HT4 receptors or any members of the 5-HT1 receptor family. Thus discovery of Ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha adrenergic receptors. It also has high affinity for H1 histaminergic receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibit 5-HT2C receptors.

Atypical antipsychotic drugs like Clozapine, Olanzapine, Quetiapine, risperidone are relatively potent antagonists of 5-HT2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are MDL-100907 (prototype of another new series of 5-HT2A antagonists) and Cyproheptadine. APD125, a new sleeping pill recently developed by Arena Pharmaceuticals and currently in Phase 2 trials, acts as a selective 5-HT2A antagonist.

Partial-agonist Antagonists
Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial agonist, in some preparations.

Genetics
The 5-HT2A receptors is coded by the HTR2A gene. Several interesting polymorphisms have been identified for this gene: -1438G/A, T102C and His452Tyr.