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|5-hydroxytryptamine (serotonin) receptor 2A|
|Locus:||13 q14 -q21|
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.
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.
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).
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.
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.[How to reference and link to summary or text]
Effects of activation of the receptor include:
- CNS: neuronal excitation, behavioural effects, learning, anxiety
- smooth muscle: contraction (in gastrointestinal tract & bronchi), suppression of TNFα mediated inflammatory processes 
- vasoconstriction / vasodilatation
- platelets: aggregation
- compound 25: high affinity and >4600-fold binding selectivity over 5-HT2C
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.
Peripherally selective agonistsEdit
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 which 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 30mg/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 Edit
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.[How to reference and link to summary or text] 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. 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 inhibit 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.
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-100,907 (prototype of another new series of 5-HT2Aantagonists) 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.
Functional selectivity Edit
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 lipophilicityEdit
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.
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.
Associations with psychiatric disorders Edit
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.
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 Edit
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.
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 endocytosisEdit
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.
- ↑ Cook EH, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL (August 1994). Primary structure of the human platelet serotonin 5-HT2A receptor: identity with frontal cortex serotonin 5-HT2A receptor. J. Neurochem. 63 (2): 465–9.
- ↑ 2.0 2.1 Elphick GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, Dugan A, Stanifer M, Bhatnagar A, Kroeze WK, Roth BL, Atwood WJ (2004). The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 306 (5700): 1380–3.
- ↑ Chapter 11, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition
- ↑ Hoyer D, Hannon J, Martin G (2002). Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71 (4): 533–54.
- ↑ Geurts FJ, De Schutter E, Timmermans JP (June 2002). Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum. Journal of chemical neuroanatomy 24 (1): 65–74.
- ↑ Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N (August 1998). Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells. Neurosci. Lett. 252 (1): 72–74.
- ↑ Maeshima T, Shiga T, Ito R, Okado N (December 2004). Expression of serotonin2A receptors in Purkinje cells of the developing rat cerebellum. Neurosci. Res. 50 (4): 411–417.
- ↑ Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007). Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320 (1): 1–13.
- ↑ 9.0 9.1 Rang, H. P. (2003). Pharmacology, Edinburgh: Churchill Livingstone. Page 187
- ↑ Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-α-Induced Inflammation with Extraordinary Potency. Journal of Pharmacology And Experimental Therapeutics. 2008;327:316-323. doi:10.1124/jpet.108.143461
- ↑ Wilson KJ, van Niel MB, Cooper L, et al (2007). 2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands. Bioorg. Med. Chem. Lett. 17 (9): 2643–8.
- ↑ Braden MR, Parrish JC, Naylor JC, Nichols DE (2006). Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Mol. Pharmacol. 70 (6): 1956–64.
- ↑ McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE (September 2006). 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of medicinal chemistry 49 (19): 5794–803.
- ↑ Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE (March 2001). Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. Journal of Medicinal Chemistry 44 (6): 1003–10.
- ↑ Sharif NA, McLaughlin MA, Kelly CR (February 2007). AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 23 (1): 1–13.
- ↑ May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA (January 2006). 1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity. Journal of medicinal chemistry 49 (1): 318–28.
- ↑ Shireman BT, Dvorak CA, Rudolph DA, Bonaventure P, Nepomuceno D, Dvorak L, Miller KL, Lovenberg TW, Carruthers NI (March 2008). 2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT2A antagonists. Bioorganic & medicinal chemistry letters 18 (6): 2103–8.
- ↑ Moya PR, Berg KA, Gutiérrez-Hernandez MA, Sáez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP (2007). Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine 5-HT2A and 5-HT2C receptors. J. Pharmacol. Exp. Ther. 321 (3): 1054–61.
- ↑ González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007). Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53 (3): 439–52.
- ↑ Schmid CL, Raehal KM, Bohn LM (2008). Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc. Natl. Acad. Sci. U.S.A. 105 (3): 1079–84.
- ↑ Abbas A, Roth BL (2008). Arresting serotonin. Proc. Natl. Acad. Sci. U.S.A. 105 (3): 831–2.
- ↑ Parker MA, Kurrasch DM, Nichols DE (2008). The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands. Bioorg. Med. Chem..
- ↑ OSIRIS search results. Gene: HTR2A. Supplementary material to article
- Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE (March 2001). Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. Journal of medicinal chemistry 44 (6): 1003–10.
- ↑ Chee IS, Lee SW, Kim JL, Wang SK, Shin YO, Shin SC, Lee YH, Hwang HM, Lim MR (2001). 5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder. Psychiatr. Genet. 11 (3): 111–114.
- ↑ Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS (2004). Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology 49 (1): 38–41.
- ↑ Williams J, Spurlock G, McGuffin P, Mallet J, Nöthen MM, Gill M, Aschauer H, Nylander PO, Macciardi F, Owen MJ (1996). Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group. The Lancet 347 (9011): 1294–1296.
- ↑ Vaquero-Lorenzo C, Baca-Garcia E, Diaz-Hernandez M, Perez-Rodriguez MM, Fernandez-Navarro P, Giner L, Carballo JJ, Saiz-Ruiz J, Fernandez-Piqueras J, Baldomero EB, de Leon J, Oquendo MA (July 2008). Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 147B (5): 645–9.
- ↑ Serretti A, Drago A, De Ronchi D (2007). HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Current medicinal chemistry 14 (19): 2053–69.
- ↑ McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am. J. Hum. Genet. 78 (5): 804–814.
- ↑ Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D, McMahon FJ (2007). Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry 164 (10): 1530–1538.
- ↑ Laje G, McMahon FJ (2007). The pharmacogenetics of major depression: past, present, and future. Biol. Psychiatry 62 (11): 1205–1207.
- ↑ Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L (1991). Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. Journal of Nuclear Medicine 32 (12): 2266–2272.
- ↑ Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn CG, Carr AA, Brunner F, Farde F (1996). 11C-MDL 100907, a radioligland for selective imaging of 5-HT2A receptors with positron emission tomography. Life Sci. 58 (10): PL 187–192.
- ↑ Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ (2004). Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography. Biological Psychiatry 55 (3): 217–24.
- ↑ Adams KH, Hansen ES, Pinborg LH, Hasselbalch SG, Svarer C, Holm S, Bolwig TG, Knudsen GM (2005). Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. International Journal of Neuropsychopharmacology 8 (3): 391–401.
- ↑ Haugbøl S, Pinborg LH, Regeur L, Hansen ES, Bolwig TG, Nielsen FA, Svarer C, Skovgaard LT, Knudsen GM (2007). Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome. Int. J. Neuropsychopharmacol. 10 (2): 245–52.
- ↑ Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, de Groot T, Schiepers C, Verbruggen A, Mortelmans L (1996). Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. Psychiatry Res. 68 (1): 11–22.
- ↑ Meltzer CC, Smith G, Price JC, Reynolds CF, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST (1998). Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction. Brain Res. 813 (1): 167–171.
- ↑ 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.
- ↑ 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.
- 5-HT2A. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
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