5-HT6 receptor

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]

HTR6
Identifiers
AliasesHTR6, 5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDsOMIM: 601109 MGI: 1196627 HomoloGene: 673 GeneCards: HTR6
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.13Start19,664,875 bp[1]
End19,680,966 bp[1]
RNA expression pattern
More reference expression data
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: 139.06 – 139.08 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Distribution

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

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

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

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).

Ligands

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

Full agonists

Partial agonists
  • 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

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

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000158748 - Ensembl, May 2017
  2. 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.
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  6. "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
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  9. 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.
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Further reading

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