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5-HT6 receptor

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HTR6
Identifiers
AliasesHTR6, 5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDsOMIM: 601109; MGI: 1196627; HomoloGene: 673; GeneCards: HTR6; OMA:HTR6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3362

15565

Ensembl

ENSG00000158748

ENSMUSG00000028747

UniProt

P50406

Q9R1C8

RefSeq (mRNA)

NM_000871

NM_021358
NM_001377096

RefSeq (protein)

NP_000862

NP_067333
NP_001364025

Location (UCSC)Chr 1: 19.66 – 19.68 MbChr 4: 138.79 – 138.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT).[5] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[5] HTR6 denotes the human gene encoding for the receptor.[6]

Distribution

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The 5HT6 receptor is expressed almost exclusively in the brain.[7] 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.[5][8][9] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[7][9][10]

Function

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Blockade of central 5HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[11][12][13][14] whereas activation enhances GABAergic signaling in a widespread manner.[15] Antagonism of 5HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[14][16] while stimulation has the opposite effect.[15]

As a drug target for antagonists

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Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[15] In parallel with this, 5HT6 antagonists are hypothesized to improve cognition, learning, and memory.[17] Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer's disease and other forms of dementia.[14][18][19] However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 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.[20][21]

As a drug target for agonists

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Recently, the 5HT6 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.[15][22] Additionally, indirect 5HT6 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]

Ligands

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A large number of selective 5HT6 ligands have now been developed.[23][24][25][26][27][28][29][30][31]

Agonists

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Full agonists

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Partial agonists

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  • E-6801[34]
  • E-6837 – partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration[35]
  • EMD-386,088 – potent partial agonist (EC50 = 1 nM) but non-selective[36][37]
  • LSD – Emax = 60%[38]

Antagonists and inverse agonists

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Genetics

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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.[45] Others have studied the polymorphism in relation to Parkinson's disease.[46]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000158748 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028747 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (January 1996). "Cloning, characterization, and chromosomal localization of a human 5HT6 serotonin receptor". Journal of Neurochemistry. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. S2CID 35874409.
  6. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
  7. ^ a b Woolley ML, Marsden CA, Fone KC (February 2004). "5HT6 receptors". Current Drug Targets. CNS and Neurological Disorders. 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245.
  8. ^ 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.
  9. ^ a b Gérard C, Martres MP, Lefèvre K, Miquel MC, Vergé D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S (January 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. S2CID 23364990.
  10. ^ Hamon M, Doucet E, Lefèvre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Vergé D (August 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5HT6 receptors". Neuropsychopharmacology. 21 (2 Suppl): 68S – 76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491.
  11. ^ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5HT, glutamate and aspartate". British Journal of Pharmacology. 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993.
  12. ^ Dawson LA, Nguyen HQ, Li P (November 2001). "The 5HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology. 25 (5): 662–8. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249.
  13. ^ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). "5HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism". Neuropharmacology. 47 (2): 195–204. doi:10.1016/j.neuropharm.2004.03.012. PMID 15223298. S2CID 1736645.
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  15. ^ 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.
  16. ^ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse. 51 (2): 158–64. doi:10.1002/syn.10288. PMID 14618683. S2CID 6539467.
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  20. ^ a b Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). "Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders". Pharmacology & Therapeutics. 117 (2): 207–31. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
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  24. ^ Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ (February 2009). "Identification of a series of benzoxazoles as potent 5-HT6 ligands". Bioorganic & Medicinal Chemistry Letters. 19 (4): 1115–7. doi:10.1016/j.bmcl.2008.12.107. PMID 19152787.
  25. ^ Lee M, Rangisetty JB, Pullagurla MR, Dukat M, Setola V, Roth BL, Glennon RA (March 2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorganic & Medicinal Chemistry Letters. 15 (6): 1707–11. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826.
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  27. ^ Benhamú B, Martín-Fontecha M, Vázquez-Villa H, Pardo L, López-Rodríguez ML (2014). "Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease". J. Med. Chem. 57 (17): 7160–81. doi:10.1021/jm5003952. PMID 24850589.
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  30. ^ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5HT6 receptor ligands". Organic & Biomolecular Chemistry. 6 (20): 3795–810. doi:10.1039/b808641a. PMID 18843410.
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Further reading

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

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