5-HT6 receptor

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Aliases HTR6, 5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDs MGI: 1196627 HomoloGene: 673 GeneCards: 3362
Targeted by Drug
EMD-386088, WAY-181187, 5-CT, 5-hydroxytryptamine, 5-MeOT, bromocriptine, dimethyltryptamine, EMDT, ergotamine, LSD, RU 24969, TFMPP, xanomeline, BRL-15572, donitriptan, E6801, GR 127935, lisuride, amitriptyline, amoxapine, cerlapirdine, cyproheptadine, duloxetine, iloperidone, mesulergine, metergoline, methiothepin, methysergide, mianserin, risperidone, ritanserin, Ro 04-6790, SB258585, SB 271046, SB357134, SB399885, sumatriptan, tiospirone, vortioxetine, chlorpromazine, clozapine, fluperlapine, fluphenazine, loxapine, Olanzapine, perphenazine, thioridazine, zotepine, idalopirdine[1]
RNA expression pattern
PBB GE HTR6 206944 at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 1: 19.67 – 19.68 Mb Chr 4: 139.06 – 139.08 Mb
PubMed search [2] [3]
View/Edit Human View/Edit Mouse

The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).[4] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[4] HTR6 denotes the human gene encoding for the receptor.[5]


The 5-HT6 receptor is expressed almost exclusively in the brain.[6] 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][7][8] 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.[6][8][9]


Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[10][11][12][13] whereas activation enhances GABAergic signaling in a widespread manner.[14] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[13][15] while stimulation has the opposite effect.[14]

As a drug target for antagonists[edit]

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.[14] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[16] 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.[13][17][18]

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.[19][20]

As a drug target for agonists[edit]

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.[14][21] 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).[citation needed]


A large number of selective 5-HT6 ligands have now been developed.[22][23][24][25][26][27][28][29][30]

Full agonists[edit]

Partial Agonists[edit]

Antagonists and inverse agonists[edit]


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.[44] Others have studied the polymorphism in relation to Parkinson's disease.[45]

See also[edit]


  1. ^ "Drugs that physically interact with 5-hydroxytryptamine receptor 6 view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ a b c 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. 
  5. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". 
  6. ^ a b 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. 
  7. ^ Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs R, Schwartz JC (May 1993). "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation". Biochemical and Biophysical Research Communications. 193 (1): 268–76. doi:10.1006/bbrc.1993.1619. PMID 8389146. 
  8. ^ a b Gérard C, Martres MP, Lefèvre K, Miquel MC, Vergé D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S (Jan 1997). "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research. 746 (1-2): 207–19. doi:10.1016/S0006-8993(96)01224-3. PMID 9037500. 
  9. ^ Hamon M, Doucet E, Lefèvre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Vergé D (Aug 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors". Neuropsychopharmacology. 21 (2 Suppl): 68S–76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491. 
  10. ^ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate". British Journal of Pharmacology. 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041free to read. PMID 10780993. 
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  14. ^ a b c d Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (May 2008). "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology. 33 (6): 1323–35. doi:10.1038/sj.npp.1301503. PMID 17625499. 
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Further reading[edit]

  • 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. 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 1523198free to read. 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[edit]

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