5-HT2A receptor

5-hydroxytryptamine (serotonin) receptor 2A, G protein-coupled
Identifiers
Symbols	HTR2A ; 5-HT2A; HTR2
External IDs	OMIM: 182135 MGI: 109521 HomoloGene: 68073 IUPHAR: 6 ChEMBL: 224 GeneCards: HTR2A Gene
Gene ontology Molecular function • virus receptor activity • G-protein alpha-subunit binding • serotonin receptor activity • drug binding • protein complex binding • serotonin binding • 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding Cellular component • cytosol • plasma membrane • integral component of plasma membrane • caveola • cytoplasmic membrane-bounded vesicle • axon • neuronal cell body • dendritic shaft • cell body fiber Biological process • temperature homeostasis • cellular calcium ion homeostasis • activation of phospholipase C activity • phospholipase C-activating serotonin receptor signaling pathway • serotonin receptor signaling pathway • synaptic transmission • aging • memory • cell death • positive regulation of cell proliferation • positive regulation of phosphatidylinositol biosynthetic process • regulation of dopamine secretion • phosphatidylinositol 3-kinase signaling • artery smooth muscle contraction • urinary bladder smooth muscle contraction • sleep • response to drug • negative regulation of potassium ion transport • positive regulation of MAP kinase activity • protein localization to cytoskeleton • positive regulation of fat cell differentiation • positive regulation of glycolytic process • positive regulation of vasoconstriction • viral entry into host cell • regulation of hormone secretion • behavioral response to cocaine • positive regulation of peptidyl-tyrosine phosphorylation • regulation of behavior • detection of temperature stimulus involved in sensory perception of pain • detection of mechanical stimulus involved in sensory perception of pain • release of sequestered calcium ion into cytosol • negative regulation of synaptic transmission, glutamatergic • positive regulation of ERK1 and ERK2 cascade Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3356	15558
Ensembl	ENSG00000102468	ENSMUSG00000034997
UniProt	P28223	P35363
RefSeq (mRNA)	NM_000621	NM_172812
RefSeq (protein)	NP_000612	NP_766400
Location (UCSC)	Chr 13: 46.83 – 46.9 Mb	Chr 14: 74.64 – 74.71 Mb
PubMed search	[1]	[2]

The mammalian 5-HT_2A receptor is a subtype of the 5-HT₂ receptor that 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-HT_2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first given importance as a target of serotonergic psychedelic drugs such as 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-HT_2A may be a necessary receptor for the spread of the human polyoma virus called JC virus.

Downregulation of post-synaptic 5-HT_2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and classical antipsychotics. Deceased suicidal and otherwise depressed patients have had more 5-HT_2A receptors than normal patients. These findings suggest that post-synaptic 5-HT_2A overdensity is involved in the pathogenesis of depression.

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-HT_2A 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-HT_1C and thus were clubbed together, renaming the 5-HT₂ into 5-HT_2A. Thus the 5-HT₂ receptor family is composed of three separate molecular entities: the 5-HT_2A (formerly known as 5-HT₂ or D), the 5-HT_2B (formerly known as 5-HT_2F) and the 5-HT_2C (formerly known as 5-HT_1C) receptors.

Distribution

5-HT_2A 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 the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory,and attention by enhancing glutamate release followed by a complex range of interactions with the 5-HT_1A, GABA_A, adenosine A₁, AMPA, mGluR_2/3, mGlu5, and OX₂ receptors. In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells.

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT_2A mRNA expression has been observed in human monocytes.

Signaling cascade

The 5-HT_2A receptor is known primarily to couple to the Gα_q signal transduction pathway. Upon receptor stimulation with agonist, Gα_q and β-γ subunits dissociate to initiate downstream effector pathways. Gα_q 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 phospholipase D, Rho/Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor.

Effects

Physiological processes mediated by the receptor include:

• CNS: neuronal excitation, behavioural effects, learning, anxiety
• smooth muscle: contraction (in gastrointestinal tract & bronchi)
• vasoconstriction / vasodilation
• platelets: aggregation
• Activation of the 5-HT_2A receptor with DOI produces potent anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT_2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation.
• Activation of the 5-HT_2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.
• Role in memory

Ligands

Agonists

Activation of the 5-HT_2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT_2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT_2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT_2A–mGlu2 and not by monomeric 5-HT_2A receptors. Agonists enhance dopamine in PFC, enhances memory and plays a role in attention and learning.

Full agonists

• 25I-NBOH and its 2-methoxy-analog 25I-NBOMe
• (R)-DOI
• TCB-2
• Bromo-DragonFLY
• Mexamine is a full agonist to several serotonin receptors.
• O-4310, 5-HT_2A selective, claimed to have 100x selectivity over 5-HT_2C and be inactive at 5-HT_2B
• PHA-57378, dual 5-HT_2A / 5-HT_2C agonist, anxiolytic effects in animal studies.

Partial agonists

• 25C-NBOMe
• Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT_2A and 5-HT_2C receptors, but sometimes acts as partial agonist, in some preparations.
• OSU-6162 acts as a partial agonist at both 5-HT_2A and dopamine D₂ receptors
• 25CN-NBOH, 100x selectivity for 5-HT_2A over 5-HT_2C, 46x selectivity over 5-HT_2B.
• Juncosamine, is a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124x selectivity for 5-HT_2A over 5-HT_2C, making it the most selective agonist ligand identified to date.
• Cannabidiol, a phytocannabinoid in Cannabis.
• Efavirenz, an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT_2A.
• Mefloquine, an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT_2A and/or 5-HT_2C receptors.
• Lisuride, an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT_2A / 5-HT_2C agonist and 5-HT_2B antagonist.

Peripherally selective agonists

One effect of 5-HT_2A receptor activation is a reduction in intraocular pressure, and so 5-HT_2A agonists can be useful for the treatment of glaucoma. This has led to the development of compounds such as AL-34662 that are hoped to reduce pressure inside the eyes but without crossing the blood–brain barrier and producing hallucinogenic side effects. Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the head-twitch response known to be characteristic of hallucinogenic effects in rodents.

Silent antagonists

• Trazodone is a potent 5-HT2A antagonist, as well as an antagonist on other serotonin receptors.
• 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.
• The 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 alpha₁ adrenergic receptors. It also has high affinity for H₁ histaminergic receptors equal to that at 5-HT_2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT_2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT_2A receptor antagonists, also potently inhibits 5-HT_2C receptors.
• Nefazodone 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 and asenapine are relatively potent antagonists of 5-HT_2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are MDL-100,907 (prototype of another new series of 5-HT_2A antagonists) and cyproheptadine.
• Pizotifen is a non-selective antagonist.
• LY-367,265 - dual 5-HT_2A antagonist / SSRI with antidepressant effects
• 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).
• AMDA and related derivatives are another family of selective 5-HT_2A antagonists.
• Hydroxyzine (Atarax)
• 5-MeO-NBpBrT

Inverse agonists

• AC-90179 - potent and selective inverse agonist at 5-HT_2A, also 5-HT_2C antagonist.
• Nelotanserin (APD-125) - selective 5-HT_2A inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.
• Eplivanserin (Sanofi Aventis), a sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT_2A inverse agonist.
• Pimavanserin (ACP-103) - more selective than AC-90179, orally active, antipsychotic in vivo, now in human clinical trials.
• Volinanserin

Functional selectivity

5-HT_2A-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-HT_2A agonists that produce headshakes in the mouse and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT_2A agonists. One known example of differences in signal transduction is between the two 5-HT_2A agonists serotonin and DOI that involves differential recruitment of 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.

Genetics

Chromosome 13.

The 5-HT_2A 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: A-1438G (rs6311), C102T (rs6313) and His452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.

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 studied in relation to suicide attempts, with a study finding excess of the C/C genotypes among the suicide attempters. A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies [of HTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.

Treatment response

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—termed rs7997012—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.

One study has also linked abnormal 5-HT_2A polymorphisms which may enhance receptor activity with Chronic Fatigue Syndrome.

Neuroimaging

The 5-HT_2A 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-HT_2A receptors with age. A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait neuroticism as measured by the NEO PI-R personality questionnaire.

Role in virus endocytosis

5-HT_2A may 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 such as oligodendrocytes, astrocytes, B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked sialic acid component of the 5-HT_2A receptor in order to endocytose JCV.

External links

• 5-HT2A Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)