5-hydroxytryptamine 2A receptor

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Revision as of 06:05, 16 February 2009

Description

The mammalian 5-HT_2A 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-HT_2A receptor". J. Neurochem. 63 (2): 465–9. doi:10.1046/j.1471-4159.1994.63020465.x. PMID 8035173. </ref> This is the main excitatory receptor subtype among the GPCRs for serotonin (5-HT), although 5-HT_2A 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-HT_2A 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:10.1126/science.1103492. PMID 15550673. </ref>

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 <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-HT_1C and thus were clubbed together, renaming the 5-HT₂ into 5-HT_2A. Thus the 5-HT₂ receptor family is comprised of three separate molecular entities: the 5-HT_2A (erstwhile 5-HT₂ or D), the 5-HT_2B (erstwhile 5-HT_2F) and the 5-HT_2C (erstwhile 5-HT_1C) 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:10.1016/S0091-3057(01)00746-8. PMID 11888546. </ref>

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 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:10.1016/S0891-0618(02)00020-0. 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:10.1016/S0304-3940(98)00546-1. 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:10.1016/j.neures.2004.08.010. 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.

Signalling 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.<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:10.1124/jpet.106.104463. 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

Source Organism

Bos taurus (Bovine).

Taxomomy

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;Pecora; Bovidae; Bovinae; Bos.

Subcellular Localization

Cell membrane; multi-pass membrane protein (By similarity). Note=Localizes to the post-synaptic thickening of axo-dendritic synapses (By similarity).

Developmental Stage

Similarity

Belongs to the G-protein coupled receptor 1 family.

Post translational Modification

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).

Categories:Receptors