5-HT6 receptor

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

Distribution

The 5-HT₆ receptor is expressed almost exclusively in the brain. 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. 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.

Function

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

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. In parallel with this, 5-HT₆ antagonists improve cognition, learning, and memory, 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. 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.

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. 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.

Full agonists

• 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)
• WAY-181,187
• WAY-208,466
• N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (compound 11q)
• N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): K_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98%
• E-6837 - Full agonist at human 5-HT₆ receptors

Partial Agonists

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

Antagonists

• BVT-5182
• BVT-74316
• Cerlapirdine - selective
• EGIS-12233 - mixed 5-HT₆ / 5-HT₇ antagonist
• Idalopirdine (Lu AE58054) - selective
• Intepirdine (SB-742,457) - selective
• Latrepirdine (non-selective) and analogues
• 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

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. Others have studied the polymorphism in relation to Parkinson's disease.

See also

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

External links

• 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.