Disease relevance of HTR6

• Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease [1].
• Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats [2].

Psychiatry related information on HTR6

• Association analysis of HTR6 and HTR2A polymorphisms in sporadic Alzheimer's disease [3].
• In addition, the HTR6 T267C polymorphism has been linked to risperidone response for positive symptoms (delusions and hallucinations) [4].
• Polymorphisms of the 5-HT6 receptor have been implicated in syndromes that affect cognition, such as schizophrenia and dementia [5].
• BGC20-761, a novel tryptamine analog, enhances memory consolidation and reverses scopolamine-induced memory deficit in social and visuospatial memory tasks through a 5-HT6 receptor-mediated mechanism [6].
• In a population-based association study, we tested the hypothesis that the allelic variant, C267T, of the human 5-HT6 gene confers susceptibility to schizophrenic disorders and associated aggressive behavior [7].

High impact information on HTR6

• Subtypes 5-HT6 and 5-HT7 couple to stimulation of adenylyl cyclases through Gs and display high affinities for antipsychotic and antidepressant drugs [8].
• To better understand how serotonin might control cAMP levels in the brain, we coexpressed 5-HT6 or 5-HT7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells [8].
• In the brain, mRNA for 5-HT6 is found at high levels in the hippocampus, striatum, and nucleus accumbens [8].
• A five SNP CACCC haplotype in HTR6 was a strong protective factor against SI (OR=0.26; P=0.007) [9].
• Manipulation of 5-HT6 receptor activity alters the transmission of several neurotransmitters important in memory: acetylcholine and glutamate, as well as dopamine, ã-aminobutyric acid (GABA), epinephrine (E), and norepinephrine (NE) [5].

Chemical compound and disease context of HTR6

• Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia [10].

Biological context of HTR6

• No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55) [11].
• The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites [12].
• Identification of a human 5-HT6 receptor variant produced by alternative splicing [13].
• Hologram quantitative structure activity relationship studies on 5-HT6 antagonists [14].
• SmithKline Beecham is developing the 5-HT6 antagonist, SB-271046, as a potential cognition enhancer [15].

Anatomical context of HTR6

• No expression of 5-HT1D beta and 5-HT6 was observed in any of the cell lines studied [16].
• Clozapine downregulates 5-hydroxytryptamine6 (5-HT6) and upregulates 5-HT7 receptors in HeLa cells [17].
• Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients [18].
• In aging control patients, the 5-HT6 receptor was expressed by pyramidal cells and occasional stellate cells, not only of layers II-V, but also of layer I, where a distinct label was observed in neurons and surrounding fibers [18].
• Intrinsic activity of these 5-HT6 receptor ligands at a constitutively active human S267K 5-HT6 receptor in Cos-7 cells indicated similar efficacy (E(max), % over basal) for 5-HT (97), E-6801 (91) and E-6837 (100), while Ro 04-6790 (-33) and SB-271046 (-39) were equi-efficacious inverse agonists [19].

Associations of HTR6 with chemical compounds

• Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia [11].
• Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders [20].
• In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors [21].
• When the corresponding residue of the 5-HT6 receptor (Ala154) was converted to serine, no change in the affinity of twelve 5-HT6 receptor ligands or in the potency of 5-HT and LSD could be detected, suggesting that this position does not contribute to the ligand binding site of the 5-HT6 receptor [22].
• No association of 5-HT2C, 5-HT6, and tryptophan hydroxylase-1 gene polymorphisms with personality traits in the Japanese population [23].

Physical interactions of HTR6

• Characterization of the 5-HT6 receptor coupled to Ca2+ signaling using an enabling chimeric G-protein [24].

Other interactions of HTR6

• In order to identify gene variants related to the serotonergic neurotransmitter system that possibly represent a hereditary risk factor for sporadic Alzheimer's disease (AD), patients suffering from AD and non-demented psychiatric inpatients without symptoms of dementia were genotyped for polymorphisms of HTR6 (267C/T) and HTR2A (-1438G/A) [3].
• At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs [25].
• Risperidone (a widely used atypical antipsychotic agent) and several other atypicals have high affinities for 5-HT6 and 5-HT7 receptors [20].
• The polymorphism studied for 5-HT5A, 5-HT6, alpha1A- and alpha2A-receptors give no clear associations with the response to clozapine [26].
• Both PHA stimulated human and monkey PBMCs express mRNAs for 5-HT1(A), 5-HT1(B), 5-HT1(E), 5-HT2(A), 5-HT3, 5-HT4, 5-HT6 receptor types/subtypes [27].

Analytical, diagnostic and therapeutic context of HTR6

• The 267C/T allele of HTR6 was genotyped using PCR amplification followed by endonuclease digestion [28].
• We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis [22].
• Cellular expressions of the two serotonergic receptors 5-HT2A and 5-HT6 have therefore been determined by immunohistochemistry in the prefrontal cortex of patients with AD (n=6) and normal age-matched controls (n = 7) [18].

References