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 and the orbitofrontal cortex. This receptor was given importance first as the target of psychedelic drugs like LSD. Later it came back to prominence because 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 the spread of the human polyoma virus called JC virus.

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 Gaddum and Picarelli. In the pre-molecular-cloning 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 is comprised of three separate molecular entities: the 5-HT2A (erstwhile 5-HT2 or D), the 5-HT2B (erstwhile 5-HT2F) and the 5-HT2C (erstwhile 5-HT1C) receptors.

Distribution
5-HT2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and olfactory tubercle. There are especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex that may modulate cognitive processes. The protein has also been found in the Golgi cells of the granular layer in the rat cerebellum, as well as in the Purkinje cells (also in the rat cerebellum).

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascularsystem, as well as in fibroblasts, and within neurons of the peripheral nervous system.

Signalling Cascade
The 5-HT2A receptor is known primarily to couple to the Gaphaq signal transduction pathway. Upon receptor stimulation with agonist, Gaphaq and beta-gamma subunits dissociate to initiate downstream effector pathways. Galphaq 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.

There are many additional signal cascade components that include the formation of arachidonic acid through PLA2 activity, activation of PLD, Rho/RhoK, and ERK pathway activation initiated by agonist stimulation of the receptor.

Effects
Effects of activation of the receptor include:
 * CNS: neuronal excitation, behavioural effects, learning, anxiety
 * smooth muscle: contraction (in gastrointestinal tract & bronchi)
 * vasoconstriction / vasodilatation
 * platelets: aggregation

Functional selectivity
5-HT2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce headshakes in the mouse and those that do not. The difference in signal transduction between the two 5-HT2A agonists serotonin and DOI may be due to the presence of the intracellular proteins called β-arrestins, more specifically arrestin beta 2.

Role of lipophilicity
A set of ligands were evaluated. For "agonists", a highly significant linear correlation was observed between binding affinity and lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity.

"Agonists"
Activation of the 5-HT2A receptor is necessary for the effects of the "classic" hallucinogens like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity.

N-(2-hydroxybenzyl)-2C-I and its 2-methoxy-analog are highly potent agonists at the human 5-HT2A receptor, as are the benzocyclobutene derivative TCB-2 and the benzodifuran derivative Br-DFLY.
 * Full agonists

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.
 * Partial agonists

"Silent antagonists"
Although 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.

Nefazadone operates by blocking post-synaptic serotonin type-2A receptors and to a lesser extent by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake.

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.

Pizotifen is a non-selective antagonist. 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).

Genetics
The 5-HT2A receptors is coded by the HTR2A gene. In humans the gene is located on chromosome 13. The gene has previously been called just HTR2 until the description of two related genes HTR2B and HTR2C. Several interesting polymorphisms have been identified for HTR2A: -1438G/A, T102C and His452Tyr.

Associations with psychiatric disorders
Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as bipolar disorder and major depressive disorder.

A weak link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia. This polymorphism has also been studies in relation to suicide attempts, with a study finding excess of the C/C genotypes among the suicide attempters.

One study has found that genetic variations between individuals in the HTR2A gene may to some extent account for the difference in outcome of antidepressant treatment, so that patients suffering from major depressive disorder and treated with Citalopram may benefit more than others if they have one particular genotype. In this study 768 single nucleotide polymorphism (SNP) across 68 genes were investigated and a SNP&mdash;termed rs7997012&mdash;in the second intron of the HTR2A gene showed significant association with treatment outcome.

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.

Neuroimaging
The 5-HT2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin and MDL 100,907 radioligands that binds to the neuroreceptor, e.g., one study reported a reduced binding of altanserin particularly in the hippocampus in patients with major depressive disorder. Another PET study reported increased altanserin binding in the caudate nuclei in obsessive compulsive disorder patients compared to a healthy control group.

Patients with Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls. The altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age. A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait neuroticism as measure by the NEO PI-R personality questionnaire.

In virus endocytosis
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 5HT2A receptor in order to endocytose JCV.