Disease relevance of HTR2C

• Our results complement previous studies of HTR2C in both mice and humans, and suggest the importance of genetic variation and elucidating the fine LD structure in uncovering the genetic factors of obesity [1].
• An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs [2].
• The serotonin 5-HT(2C) receptor (HTR2C) helps regulate appetite and body weight [2].
• Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women [2].
• However, pharmacological evidence and recent molecular genetic studies would suggest a role for the 5-HT2C receptor in the consequences of antipsychotic treatment, particularly in relation to the development of both drug-induced dyskinesias and weight gain [3].

Psychiatry related information on HTR2C

• These results indicate that the HTR2C promoter polymorphism does not contribute significantly to the etiopathogenesis of bipolar disorder in females [4].
• The subjects were 63 biologically unrelated patients with panic disorder and 100 biologically unrelated normal control subjects who were native Japanese living in the western area of Japan. HTR1A and HTR2C showed no significant association with panic disorder [5].
• Slow wave sleep in humans: role of 5-HT2A and 5-HT2C receptors [6].
• This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD) [7].
• In addition, another common polymorphic variation in the 5-HT2A and 5-HT2C serotonin receptor genes previously analyzed in schizophrenic patients was associated with auditory and visual hallucinations in AD [8].

High impact information on HTR2C

• Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse [9].
• Among the multiple serotonin receptors that exist in brain, at least two--5HT1A and 5HT2 or 5HT1C receptors--seem to mediate activation of pituitary-adrenocortical function [10].
• Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites) [11].
• Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims [11].
• In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD [11].

Chemical compound and disease context of HTR2C

• Evolutionary conserved microsatellites in the promoter region of the 5-hydroxytryptamine receptor 2C gene (HTR2C) are not associated with bipolar disorder in females [4].
• 5-HT2C agonism may also underlie the minimal weight gain seen with aripiprazole [12].
• BW 723C86 given either s.c. (1-20 mg/kg 30 min pre-test) or i.c.v. (1-30 micrograms) did not cause hypolocomotion, penile erection, oral dyskinesias or hyperthermia, behaviours associated with administration of the 5-HT2C/2B receptor agonist m-chlorophenylpiperazine (mCPP), and are thus likely to involve-5-HT2C receptor activation [13].
• We studied the effects of the 5-HT2 receptor antagonists, ritanserin and ketanserin, on the sleep of healthy volunteers in order to clarify the role of 5-HT2A and 5-HT2C receptors in the regulation of slow wave sleep (SWS) in humans [6].
• The 9Gly-variant of the dopamine D3 receptor, the 102C-variant, but not the His452Tyr polymorphism of the 5-HT2A-receptor and the 23Ser-variant (for females only) of the 5-HT2C receptor seem to increase the susceptibility to tardive dyskinesia [14].

Biological context of HTR2C

• Significant haplotype associations were found in all but the HTR1A and HTR2C genes [15].
• We suggest that inconsistent associations between HTR2C and several phenotypes, including obesity, may be due to the LD pattern across the gene in which recombination and gene conversion have been influential [1].
• We report a detailed investigation of linkage disequilibrium (LD) within and between the HTR2C promoter and the flanking sequences around a commonly utilized marker in the second coding exon of HTR2C [1].
• HTR2C is also located on the X chromosome [16].
• Although promoter-associated microsatellites have previously been shown to regulate expression of different genes, we did not find any significant influence of distinct HTR2C promoter microsatellite alleles on transcriptional efficiency as measured by luciferase activity and receptor availability as assayed by [(3)H]-mesulergine binding [4].

Anatomical context of HTR2C

• In Chinese hamster ovary (CHO) cells stably expressing 5-HT2 receptors, aripiprazole displayed a dual agonist/antagonist profile for 5-HT2C receptor (VNI isoform) mediated calcium signaling (EC50 1070 nM, IC50 281 nM) [12].
• Since 5-HT2A and 5-HT2C receptor mRNAs are not detectable in pulmonary artery endothelial cells, activation of 5-HT2B receptors is responsible for the transient calcium release [17].
• In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 microM [18].
• Expression of wild-type 5-HT2C receptors in an S138R-expressing stable cell line had no effect on ligand binding to wild-type 5-HT2C receptors, but inhibited basal and 5-HT-stimulated IP signaling as well as constitutive and 5-HT-stimulated endocytosis of wild-type 5-HT2C receptors [19].
• Therefore, inactive 5-HT2C receptors inhibit wild-type 5-HT2C receptor function by forming nonfunctional heterodimers expressed on the plasma membrane [19].

Associations of HTR2C with chemical compounds

• In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C) [20].
• The current study examined the association between adolescent outcome in ADHD and serotonin system genes, including the -1438A>G polymorphism of the serotonin 2A receptor gene (HTR2A) and the -759C>T polymorphism of the serotonin 2C receptor gene (HTR2C) [21].
• The cyclopropylamine moiety therefore appears to be a good strategy for rigidification of the ethylamine side chain only for tryptamines that bind to the 5-HT2C receptor isoform [22].
• Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms [12].
• In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors [23].

Physical interactions of HTR2C

• Editing events at four major positions, termed A, B, C and D, as well as one minor site termed C', are predicted to alter amino acids within the second intracellular loop of the G-protein coupled 5-HT2C receptor [24].
• In view of evidence that 5HT2A and 5HT2C sites functionally interact with 5HT1A receptors, we also examined the influence of these agents upon the actions of S 15535, but no significant alteration was seen in its enhancement of rhythms [25].

Regulatory relationships of HTR2C

• 1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation [26].
• We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes [27].
• 5. Prior exposure of SH-SY5Y/5-HT2C cells to 5-HT (1 microM/15 min) caused a significant decrease in the 5-HT-stimulated peak in Ins(1,4,5)P3 levels whereas no such change occurred in SH-SY5Y/5-HT2A cells following exposure to 10 microM 5-HT for 15 min [28].

Other interactions of HTR2C

• Furthermore, the maximal response to 5-carboxytryptamine was reduced in a concentration-dependent manner by the 5-HT2A/5-HT2C-selective partial agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [29].
• The reduction of 5-HT1B-like responsiveness produced by 5-HT2C receptor activation was independent of protein kinase C activation and increases in the intracellular calcium concentration [29].
• In the current study, we examined the relationship between the C-759T and G-697C polymorphisms of HTR2C and ADHD in 488 Han Chinese families [16].
• Negative results for transmission disequilibrium of polymorphisms of HTR2C and MAOA with autism were provided from German and Austrian families [30].
• The agonist-induced [Ca2+]i mobilization in h-CM cells was potently blocked by the 5-HT2A-selective antagonist M-100907 (IC50=1.2+/-0.4 nM) but less potently by the antagonists for 5-HT2B (RS-127445, IC50>10 microM) and 5-HT2C (RS-102221, IC50=5.8+/-2.3 microM) receptors [31].

Analytical, diagnostic and therapeutic context of HTR2C

• In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status [2].
• Evidence for and against involvement of 5-HT2A and/or 5-HT2C receptors in the therapeutic effects of drug therapies for OCD are reviewed [32].
• The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays [33].
• Here we examined RNA editing efficiencies of site A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder, schizophrenia, and major depression as well as control subjects by using primer extension combined with denaturing high performance liquid chromatography [34].
• The molecular basis of ligand selectivity of hallucinogenic and nonhallucinogenic compounds of varying structural classes for the human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors was investigated with the use of reciprocal site-directed mutagenesis [35].

References