5-hydroxytryptamine 2A receptor
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[edit] Description
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).<ref name="pmid8035173">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. doi:. PMID 8035173.</ref> This is the main excitatory receptor subtype among the GPCRs for serotonin (5-HT), although 5-HT2A may also have an inhibitory effectTemplate:Fact 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.<ref name="pmid15550673">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. doi:. PMID 15550673.</ref>
[edit] 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 <ref>Chapter 11, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition </ref>. 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.<ref name=Hoyer_2002>Hoyer D, Hannon J, Martin G (2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacol Biochem Behav 71 (4): 533–54. doi:. PMID 11888546.</ref>
[edit] 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,<ref name="pmid12084412">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. doi:. PMID 12084412.</ref> as well as in the Purkinje cells (also in the rat cerebellum).<ref>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. doi:. PMID 9756362.</ref><ref>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. doi:. PMID 15567478.</ref>
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.
[edit] Signalling 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.<ref name="pmid16803859">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. doi:. PMID 16803859.</ref>
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.Template:Fact
[edit] Source Organism
Bos taurus (Bovine).
[edit] Taxomomy
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;Pecora; Bovidae; Bovinae; Bos.
[edit] Subcellular Localization
Cell membrane; multi-pass membrane protein (By similarity). Note=Localizes to the post-synaptic thickening of axo-dendritic synapses (By similarity).
[edit] Developmental Stage
[edit] Similarity
Belongs to the G-protein coupled receptor 1 family.
[edit] Post translational Modification
[edit] Ligands
- compound 25: high affinity and >4600-fold binding selectivity over 5-HT2C<ref name="pmid17314044">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. doi:. PMID 17314044.</ref>
[edit] 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.
[edit] Full agonists
N-(2-hydroxybenzyl)-2C-I and its 2-methoxy-analog are highly potent agonists at the human 5-HT2A receptor,<ref name="pmid17000863">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. doi:. PMID 17000863.</ref> as are the benzocyclobutene derivative TCB-2<ref name="pmid16970404">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. doi:. PMID 16970404.</ref> and the benzodifuran derivative Br-DFLY.<ref name="pmid11300881">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. doi:. PMID 11300881.</ref>
[edit] 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.
[edit] 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 which are hoped to reduce pressure inside the eyes but without crossing the blood-brain barrier and producing hallucinogenic side effects.<ref name="pmid17341144">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. doi:. PMID 17341144.</ref> 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.<ref name="pmid16392816">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. doi:. PMID 16392816.</ref>
[edit] 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.Template:Fact 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.
Pizotifen is a non-selective antagonist.<ref name=Rang187> Template:Cite book Page 187 </ref> 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).<ref name="pmid18282705">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. doi:. PMID 18282705.</ref>
[edit] Function
This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. This receptor is involved in tracheal smooth muscle contraction, bronchoconstriction, and control of aldosterone production (By similarity).
