5-HT6 receptor

5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled
Identifiers
Symbols	HTR6 ; 5-HT6; 5-HT6R
External IDs	OMIM: 601109 MGI: 1196627 HomoloGene: 673 IUPHAR: 11 ChEMBL: 3371 GeneCards: HTR6 Gene
Gene ontology Molecular function • histamine receptor activity • serotonin receptor activity • protein binding Cellular component • plasma membrane • integral component of plasma membrane • cilium Biological process • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • serotonin receptor signaling pathway • synaptic transmission • cerebral cortex cell migration • positive regulation of TOR signaling Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3362	15565
Ensembl	ENSG00000158748	ENSMUSG00000028747
UniProt	P50406	Q9R1C8
RefSeq (mRNA)	NM_000871	NM_021358
RefSeq (protein)	NP_000862	NP_067333
Location (UCSC)	Chr 1: 19.67 – 19.68 Mb	Chr 4: 139.06 – 139.08 Mb
PubMed search

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 G_s and mediates excitatory neurotransmission.^[1] HTR6 denotes the human gene encoding for the receptor.^[2]

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.^[1][4][5] 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.^[3][5][6]

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, idalopirdine (Lu AE58054), and intepirdine (SB-742,457) are being developed as novel treatments for Alzheimer's disease and other forms of dementia.^[10][14][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.^[11][18] Additionally, indirect 5-HT₆ activation may play a 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): K_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98%^[29]
• E-6837 - Full agonist at human 5-HT₆ receptors

Partial Agonists

• E-6801^[30]
• E-6837 - partial agonist at rat 5-HT₆ receptors. Orally active in rats, and caused weight loss with chronic administration^[31]
• LSD - E_max = 60%^[32]

Antagonists

• BVT-5182^[33]
• BVT-74316^[16]
• Cerlapirdine - selective
• EGIS-12233 - mixed 5-HT₆ / 5-HT₇ antagonist
• Idalopirdine (Lu AE58054) - selective
• Intepirdine (SB-742,457) - selective
• Latrepirdine (non-selective)^[34] and analogues^[35]
• MS-245
• PRX-07034
• SB-258,585
• SB-271,046
• SB-357,134
• SB-399,885
• Ro04-6790
• Atypical antipsychotics (sertindole, olanzapine, asenapine, clozapine)
• WAY-255315 / SAM-315: K_i = 1.1 nM, IC₅₀ = 13 nM^[36]

Genetics

Polymorphisms in the HTR6 gene are associated with neuropsychiatric disorders. For example an association between the C267T (rs1805054) polymorphism and Alzheimer's disease has been shown.^[37] Others have studied the polymorphism in relation to Parkinson's disease.^[38]

See also

• 5-HT receptor
• 5-HT₁ receptor
• 5-HT₂ receptor
• 5-HT₃ receptor
• 5-HT₄ receptor
• 5-HT₅ receptor
• 5-HT₇ receptor

References

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2. "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
3. Woolley ML, Marsden CA, Fone KC (Feb 2004). "5-HT₆ receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245.
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25. Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (Oct 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT₆ receptor ligands". Organic & Biomolecular Chemistry 6 (20): 3795–810. doi:10.1039/b808641a. PMID 18843410.
26. Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (Oct 2005). "2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT₆ receptor agonists". Bioorganic & Medicinal Chemistry Letters 15 (19): 4230–4. doi:10.1016/j.bmcl.2005.06.067. PMID 16055331.
27. Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (Mar 2000). "2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors". Journal of Medicinal Chemistry 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164.
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29. Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (Feb 2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT₆ serotonin receptor agonists". Journal of Medicinal Chemistry 52 (3): 675–87. doi:10.1021/jm8009469. PMID 19159187.
30. Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (Aug 2006). "Efficacy of selective 5-HT₆ receptor ligands determined by monitoring 5-HT₆ receptor-mediated cAMP signaling pathways". British Journal of Pharmacology 148 (8): 1133–43. doi:10.1038/sj.bjp.0706827. PMC 1752021. PMID 16865095.
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32. Boess FG, Monsma FJ, Carolo C, Meyer V, Rudler A, Zwingelstein C, Sleight AJ (1997). "Functional and radioligand binding characterization of rat 5-HT₆ receptors stably expressed in HEK293 cells". Neuropharmacology 36 (4-5): 713–20. doi:10.1016/s0028-3908(97)00019-1. PMID 9225298.
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Further reading

• Hoyer D, Hannon JP, Martin GR (Apr 2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology, Biochemistry, and Behavior 71 (4): 533–54. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546.
• Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics 92 (2-3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.
• Van Oekelen D, Luyten WH, Leysen JE (Apr 2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sciences 72 (22): 2429–49. doi:10.1016/S0024-3205(03)00141-3. PMID 12650852.
• Dubertret C, Hanoun N, Adès J, Hamon M, Gorwood P (Apr 2004). "Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 126B (1): 10–5. doi:10.1002/ajmg.b.20120. PMID 15048641.
• Ullmer C, Schmuck K, Kalkman HO, Lübbert H (Aug 1995). "Expression of serotonin receptor mRNAs in blood vessels". FEBS Letters 370 (3): 215–21. doi:10.1016/0014-5793(95)00828-W. PMID 7656980.
• Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (Jan 1996). "Cloning, characterization, and chromosomal localization of a human 5-HT₆ serotonin receptor". Journal of Neurochemistry 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
• Orlacchio A, Kawarai T, Paciotti E, Stefani A, Orlacchio A, Sorbi S, St George-Hyslop PH, Bernardi G (May 2002). "Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease". Neuroscience Letters 325 (1): 13–6. doi:10.1016/S0304-3940(02)00221-5. PMID 12023056.
• Ham BJ, Kim YH, Choi MJ, Cha JH, Choi YK, Lee MS (Jan 2004). "Serotonergic genes and personality traits in the Korean population". Neuroscience Letters 354 (1): 2–5. doi:10.1016/S0304-3940(03)00753-5. PMID 14698468.
• Bernotas R, Lenicek S, Antane S, Zhang GM, Smith D, Coupet J, Harrison B, Schechter LE (Nov 2004). "1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT₆ receptor ligands". Bioorganic & Medicinal Chemistry Letters 14 (22): 5499–502. doi:10.1016/j.bmcl.2004.09.003. PMID 15482912.
• Kang H, Lee WK, Choi YH, Vukoti KM, Bang WG, Yu YG (Apr 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". Biochemical and Biophysical Research Communications 329 (2): 684–92. doi:10.1016/j.bbrc.2005.02.040. PMID 15737640.
• Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R (Aug 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature 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. PMID 16640790.
• Yun HM, Kim S, Kim HJ, Kostenis E, Kim JI, Seong JY, Baik JH, Rhim H (Feb 2007). "The novel cellular mechanism of human 5-HT₆ receptor through an interaction with Fyn". The Journal of Biological Chemistry 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.
• serotonin 6 receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.