5-HT6 receptor
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| 5-hydroxytryptamine (serotonin) receptor 6 | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | HTR6; 5-HT6; 5-HT6R | ||||||||||||
| External IDs | OMIM: 601109 MGI: 1196627 HomoloGene: 673 IUPHAR: 5-HT6 GeneCards: HTR6 Gene | ||||||||||||
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| RNA expression pattern | |||||||||||||
| 250px | |||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 3362 | 15565 | |||||||||||
| Ensembl | ENSG00000158748 | ENSMUSG00000028747 | |||||||||||
| UniProt | P50406 | Q14AW8 | |||||||||||
| RefSeq (mRNA) | NM_000871 | NM_021358 | |||||||||||
| RefSeq (protein) | NP_000862 | NP_067333 | |||||||||||
| Location (UCSC) | Chr 1: 19.86 - 19.88 Mb | Chr 4: 138.33 - 138.35 Mb | |||||||||||
| PubMed search | [1] | [2] | |||||||||||
The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).[1] It is a G protein-coupled receptor (GPCR) that is coupled to Gs/Go and mediates excitatory neurotransmission.[1] HTR6 denotes the human gene encoding for the receptor.[2]
Contents
Distribution
The 5-HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[4][5][1] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[5][6][3]
Function
Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]
Despite the 5-HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[13] and agents such as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other dementias.[14][10][15] 5-HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]
Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[18][11] Additionally, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).
Ligands
A large number of selective 5-HT6 ligands have now been developed and this is a productive current area of research.[19][20][21][22][23][24][25]
Full agonists
- EMD-386,088 - potent and selective 5HT6 agonist (EC50 1nM)[26]
- 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)[27]
- WAY-181,187[11]
- WAY-208,466[11]
- N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (compound 11q)[28]
- N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%[29]
Partial Agonists
Antagonists
- BVT-5182[32]
- BVT-74316[16]
- EGIS-12233 - mixed 5-HT6 / 5-HT7 antagonist
- Latrepirdine (non-selective)[33] and analogues[34]
- Lu AE58054
- MS-245
- PRX-07034
- SB-258,585
- SB-271,046
- SB-357,134
- SB-399,885
- SB-742,457
- Ro04-6790
Genetics
The receptor is encoded by the HTR6 gene. As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain, and research studies have investigated whether polymorphisms is associated with brain-related variables, such as neuropsychiatric disorders. For example, in 2004 one Chinese study reported an association between the C267T (rs1805054) polymorphism and Alzheimer's disease.[35] Others have studied the polymorphism in relation to Parkinson's disease.[36]
See also
References
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- Hoyer D, Hannon JP, Martin GR (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.
- Raymond JR, Mukhin YV, Gelasco A; et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacol. Ther. 92 (2-3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.
- Van Oekelen D, Luyten WH, Leysen JE (2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sci. 72 (22): 2429–49. doi:10.1016/S0024-3205(03)00141-3. PMID 12650852.
- Dubertret C, Hanoun N, Adès J; et al. (2004). "Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia". Am. J. Med. Genet. B Neuropsychiatr. Genet. 126 (1): 10–5. doi:10.1002/ajmg.b.20120. PMID 15048641.
- Ullmer C, Schmuck K, Kalkman HO, Lübbert H (1995). "Expression of serotonin receptor mRNAs in blood vessels". FEBS Lett. 370 (3): 215–21. doi:10.1016/0014-5793(95)00828-W. PMID 7656980.
- Kohen R, Metcalf MA, Khan N; et al. (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". J. Neurochem. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
- Orlacchio A, Kawarai T, Paciotti E; et al. (2002). "Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease". Neurosci. Lett. 325 (1): 13–6. doi:10.1016/S0304-3940(02)00221-5. PMID 12023056.
- Strausberg RL, Feingold EA, Grouse LH; et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241 Freely accessible. PMID 12477932.
- Ham BJ, Kim YH, Choi MJ; et al. (2004). "Serotonergic genes and personality traits in the Korean population". Neurosci. Lett. 354 (1): 2–5. doi:10.1016/S0304-3940(03)00753-5. PMID 14698468.
- Bernotas R, Lenicek S, Antane S; et al. (2005). "1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands". Bioorg. Med. Chem. Lett. 14 (22): 5499–502. doi:10.1016/j.bmcl.2004.09.003. PMID 15482912.
- Gerhard DS, Wagner L, Feingold EA; et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928 Freely accessible. PMID 15489334.
- Kang H, Lee WK, Choi YH; et al. (2005). "Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the alpha subunit of GS protein". Biochem. Biophys. Res. Commun. 329 (2): 684–92. doi:10.1016/j.bbrc.2005.02.040. PMID 15737640.
- Tao WA, Wollscheid B, O'Brien R; et al. (2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nat. Methods. 2 (8): 591–8. doi:10.1038/nmeth776. PMID 16094384.
- Lorke DE, Lu G, Cho E, Yew DT (2006). "Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients". BMC neuroscience. 7: 36. doi:10.1186/1471-2202-7-36. PMC 1523198 Freely accessible. PMID 16640790.
- Yun HM, Kim S, Kim HJ; et al. (2007). "The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn". J. Biol. Chem. 282 (8): 5496–505. doi:10.1074/jbc.M606215200. PMID 17189269.
External links
- "5-HT6". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- MeSH serotonin+6+receptor
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
- ↑ 1.0 1.1 1.2 Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". J. Neurochem. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
- ↑ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
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- ↑ Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry. 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131.
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- ↑ Lee M, Rangisetty JB, Pullagurla MR; et al. (2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorg. Med. Chem. Lett. 15 (6): 1707–11. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826.
- ↑ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (2006). "Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors". J. Med. Chem. 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710.
- ↑ Zhou P, Yan Y, Bernotas R; et al. (2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorg. Med. Chem. Lett. 15 (5): 1393–6. doi:10.1016/j.bmcl.2005.01.005. PMID 15713394.
- ↑ Ahmed M, Briggs MA, Bromidge SM; et al. (2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 15 (21): 4867–71. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522.
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- ↑ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). "2-Substituted tryptamines: agents with selectivity for 5-HT6 serotonin receptors". J. Med. Chem. 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164.
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- ↑ Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". J. Med. Chem. 52 (3): 675–87. doi:10.1021/jm8009469. PMID 19159187.
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- ↑ Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. Molecular Neurodegeneration. 2008 Oct 21;3-15. PMID 18939977
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