5-HT_2A receptor

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).[4] 5-HT is short for 5-hydroxy-tryptamine, which is serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT_2A may also have an inhibitory effect[5] on certain areas such as the visual cortex and the orbitofrontal cortex.[6] This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. 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.

HTR2A
Identifiers
Aliases	HTR2A, 5-HT2A, HTR2, 5-hydroxytryptamine receptor 2A
External IDs	OMIM: 182135 MGI: 109521 HomoloGene: 68073 GeneCards: HTR2A
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q14.2 Start 46,831,550 bp[1] End 46,897,076 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding • G-protein coupled receptor activity • virus receptor activity • signal transducer activity • drug binding • G-protein alpha-subunit binding • G-protein coupled serotonin receptor activity • serotonin binding • neurotransmitter receptor activity • GO:0001948 protein binding • GO:0032403 macromolecular complex binding Cellular component • cytoplasm • integral component of membrane • cytosol • cell projection • membrane • cell body fiber • integral component of plasma membrane • dendritic shaft • axon • neuronal cell body • caveola • cytoplasmic vesicle • cell membrane • dendrite • glutamatergic synapse • integral component of postsynaptic membrane • integral component of presynaptic membrane Biological process • detection of mechanical stimulus involved in sensory perception of pain • release of sequestered calcium ion into cytosol • regulation of dopamine secretion • phospholipase C-activating serotonin receptor signaling pathway • urinary bladder smooth muscle contraction • positive regulation of MAP kinase activity • behavioral response to cocaine • positive regulation of cytosolic calcium ion concentration • positive regulation of kinase activity • positive regulation of phosphatidylinositol biosynthetic process • aging • cellular calcium ion homeostasis • cell death • memory • activation of phospholipase C activity • detection of temperature stimulus involved in sensory perception of pain • protein localization to cytoskeleton • sleep • positive regulation of vasoconstriction • positive regulation of cell proliferation • negative regulation of potassium ion transport • positive regulation of ERK1 and ERK2 cascade • artery smooth muscle contraction • positive regulation of peptidyl-tyrosine phosphorylation • viral entry • phosphatidylinositol 3-kinase signaling • nociception • temperature homeostasis • GO:0022415 viral process • positive regulation of fat cell differentiation • positive regulation of glycolytic process • negative regulation of synaptic transmission, glutamatergic • signal transduction • chemical synaptic transmission • response to drug • serotonin receptor signaling pathway • phospholipase C-activating G-protein coupled receptor signaling pathway • G-protein coupled receptor signaling pathway • animal behavior • regulation of synaptic vesicle exocytosis • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3356	15558
Ensembl	ENSG00000102468	n/a
UniProt	P28223	P35363
RefSeq (mRNA)	NM_001165947 NM_000621 NM_001378924	NM_172812
RefSeq (protein)	NP_000612 NP_001159419 NP_001365853	NP_766400
Location (UCSC)	Chr 13: 46.83 – 46.9 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

5-HT_2A may be a necessary receptor for the spread of the human polyoma virus called the JC virus.[7]

Downregulation of post-synaptic 5-HT_2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. 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.[8]

Paradoxical down-regulation of 5-HT_2A receptors can be observed with several 5-HT_2A antagonists.[9] Thus, instead of tolerance, reverse-tolerance would be expected from 5-HT_2A antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT_2A receptors.[9][10] Additionally, a couple of other antagonists may have no effect on 5-HT_2A receptor number.[11] Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the SWS promoting effects of 5-HT_2A antagonists.[12]

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.[13] 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.[14] 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.[15]

Distribution

5-HT_2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotonergic 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[16][17][18] by enhancing glutamate release followed by a complex range of interactions with the 5-HT_1A,[19] GABA_A,[20] adenosine A₁,[21] AMPA,[22] mGluR_2/3,[23] mGlu5,[24] and OX₂ receptors.[25][26] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,[27] and in the Purkinje cells.[28][29]

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.[30] Whole-body distribution of the 5-HT2A/2C receptor agonist, [11C]Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT2A receptor binding.[31]

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.[32]

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 (most likely responsible for the psychedelic effects associated with 5-HT_2A receptor agonists such as LSD, DMT, etc.),[33] behavioural effects, learning, anxiety, and pro-nociception[34]
• smooth muscle: contraction (in bronchi and gastrointestinal tract)
• vasoconstriction / vasodilation
• platelets: aggregation
• Activation of the 5-HT_2A receptor with 2,5-Dimethoxy-4-iodoamphetamine (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.[35][36]
• Activation of the 5-HT_2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.[37][38]
• Role in memory and learning[18][39][40]
• Light and color perception
• Regulation of emotion

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.[41][42] 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.[43][44][33] Agonists enhance dopamine in PFC,[18] enhance memory and play an active role in attention and learning.[45][46]

Full agonists

• Agmatine
• 25I-NBOH and its 2-methoxy-analog 25I-NBOMe[47]
• ¹⁸F FECIMBI-36, radiolabelled agonist ligand for mapping 5-HT_2A / 5-HT_2C receptor distribution[48]
• TCB-2[49]
• 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.[50]
• 25B-NBOMe Also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT_2A receptor[51]

Partial agonists

• 25C-NBOMe
• 25CN-NBOH, 100x selectivity for 5-HT_2A over 5-HT_2C, 46x selectivity over 5-HT_2B.[52]
• Bromo-DragonFLY[53]
• (R)-DOI, traditionally the most common 5-HT_2A reference agonist used in research[54]
• Efavirenz, an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT_2A.[55]
• 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.[56]
• Lisuride, an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT_2A / 5-HT_2C agonist[57] and 5-HT_2B antagonist.[58]
• Mefloquine, an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT_2A and/or 5-HT_2C receptors.[59]
• 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
• SN-22, partial agonist at all three 5-HT₂ subtypes

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.[60] 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.[61]

Silent antagonists

• Trazodone is a potent 5-HT_2A antagonist, as well as an antagonist on other serotonin receptors.
• Mirtazapine is a 5-HT_2A, 5-HT_2C, and 5-HT₃ antagonist. Mirtazapine also has an antagonistic effect on H₁ histamine receptors. Because of its wide spectrum of serotonergic receptor inhibition, Mirtazapine exhibits an agonistic effect on 5-HT_1A receptors by funneling more serotonin to them. Mirtazapine is used as an antidepressant in patients dealing with insomnia and weight loss.
• 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.[62]
• 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).[63]
• AMDA and related derivatives are another family of selective 5-HT_2A antagonists.[64][65][66][67][68]
• Typical antipsychotics such as Haloperidol and Chlorpromazine
• Hydroxyzine (Atarax)
• 5-MeO-NBpBrT
• Niaprazine

Inverse agonists

• AC-90179 - potent and selective inverse agonist at 5-HT_2A, also 5-HT_2C antagonist.[69][70]
• 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.[71]
• 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 FDA approved for the treatment of hallucinations and delusions associated with Parkinson's disease.[72][73][74][75][76]
• 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.[77]

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.[78][79] 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.[80][81]

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.[82]

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.[83][53]

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as bipolar disorder[84] and major depressive disorder.[85] A weak link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.[86] 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.[87] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[88]

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.[89]

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.[90] 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.[91][92]

One study has also linked abnormal 5-HT_2A polymorphisms which may enhance receptor activity with chronic fatigue syndrome.[93]

Neuroimaging

The 5-HT_2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin[94] , MDL 100,907[95] or [¹¹C]Cimbi-36[51][96] 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.[97] Another PET study reported increased altanserin binding in the caudate nuclei in obsessive compulsive disorder patients compared to a healthy control group.[98]

Patients with Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls.[99] The altanserin uptake decreases with age reflecting a loss of specific 5-HT_2A receptors with age.[100][101][102] 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.[103]

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.[7]

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Further reading

• Perez-Aguilar JM, Shan J, LeVine MV, Khelashvili G, Weinstein H (November 2014). "A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2". Journal of the American Chemical Society. 136 (45): 16044–54. doi:10.1021/ja508394x. PMC 4235374. PMID 25314362.

External links

• "5-HT_2A". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• _2A%20Receptor 5-HT_2A+Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human HTR2A genome location and HTR2A gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P28223 (5-hydroxytryptamine receptor 2A) at the PDBe-KB.