5-HT2A receptor

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5-hydroxytryptamine (serotonin) receptor 2A
Identifiers
SymbolsHTR2A; 5-HT2A; HTR2
External IDsOMIM: 182135 MGI: 109521 HomoloGene: 68073 IUPHAR: 5-HT2A GeneCards: HTR2A Gene
RNA expression pattern
250px
250px
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez335615558
EnsemblENSG00000102468ENSMUSG00000034997
UniProtP28223Q543D4
RefSeq (mRNA)NM_000621NM_172812
RefSeq (protein)NP_000612NP_766400
Location (UCSC)Chr 13:
46.31 - 46.37 Mb		Chr 14:
73.37 - 73.44 Mb
PubMed search[1][2]

The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR).[1] This is the main excitatory receptor subtype among the GPCRs for serotonin (5-HT), although 5-HT2A may also have an inhibitory effect[citation needed] 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.[2]

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.[3] 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.[citation needed] 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 composed 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.[4]

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 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,[5][6][7] by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A,[8] GABAA,[9] adenosine A1,[10] AMPA,[11] mGluR2/3,[12] mGlu5,[13] and OX2 receptors.[14][15] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,[16] and in the Purkinje cells.[17][18]

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

Signaling cascade

The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq 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.[19]

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

Effects

Physiological processes mediated by the receptor include:

Ligands

Agonists

Activation of the 5-HT2A 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-HT2A 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.[21][22] 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.

Full agonists

Partial 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.

Peripherally selective agonists

One effect of 5-HT2A receptor activation is a reduction in intraocular pressure, and so 5-HT2A 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.[26] 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.[27]

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.
  • Ketanserin, the prototypic 5-HT2 receptor antagonist potently blocks 5-HT2Areceptors, 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.[citation needed] 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 alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A 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 inhibits 5-HT2C 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.
  • 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).[29]

Inverse agonists

  • AC-90179 - potent and selective inverse agonist at 5-HT2A, also 5-HT2C antagonist.[35][36]
  • APD-125 - selective 5-HT2A inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials,[37] but development of APD-125 was halted in December 2008 because the substance did not meet the trial's endpoints.[38]
  • 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-HT2A inverse agonist.

Examples

Agonists Antagonists

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.[43]
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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, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists.[44][45] 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.[46][47]

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.[48]

Genetics

File:Chromosome 13.jpeg
Chromosome 13.

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: A-1438G (rs6311), C102T (rs6313) and His452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.[49]

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as bipolar disorder[50] and major depressive disorder.[51] A weak link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.[52] 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.[53] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[54]

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.[55]

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.[56] 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.[57][58]

Neuroimaging

The 5-HT2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin[59] and MDL 100,907[60] 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.[61] Another PET study reported increased altanserin binding in the caudate nuclei in obsessive compulsive disorder patients compared to a healthy control group.[62]

Patients with Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls.[63] The altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age.[64][65][66] 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.[67]

Role In virus endocytosis

5-HT2A is 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.[2]

References

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External links

  • "5-HT2A". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened
Key concepts
Processes
Signaling pathways
Agents
Other
ru:5-HT2A-рецептор
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  66. ↑ Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbøl S, Madsen K, Frøkjaer V, Martiny L, Olaf B. Paulson, Knudsen GM (2004). "A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables". NeuroImage. 21 (3): 1105–1113. doi:10.1016/j.neuroimage.2003.10.046. PMID 15006678. 
  67. ↑ Frøkjær VG, Mortensen EL, Nielsen FÅ, Haugbøl S, Pinborg LH, Adams KH, Svarer C, Hasselbalch SG, Holm S, Paulson OB, Knudsen GM (2008). "Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder". Biological Psychiatry. 63 (6): 569–76. doi:10.1016/j.biopsych.2007.07.009. PMID 17884017. 
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