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HTR6
Identifiers
Aliases HTR6, 5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDs OMIM: 601109 MGI: 1196627 HomoloGene: 673 GeneCards: HTR6
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 Mb Chr 4: 138.79 – 138.8 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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).[ citation needed]

Ligands

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

Agonists

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000158748 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028747 – Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading

External links

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

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