Disease relevance of HTR3A

• Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients [1].
• Here, we show that PKC potentiated 5-HT3 receptor-mediated current in Xenopus oocytes expressing 5-HT3A receptors and mouse N1E-115 neuroblastoma cells [2].
• Two subunits, the 5-HT3A and 5-HT3B are expressed in anatomical structures known to be involved in the mechanism of acute cytostatic drug induced emesis [3].
• 5-HT3 antagonists are used to prevent emesis from cancer chemotherapy and also demonstrate efficacy in radiation-induced nausea, postoperative nausea, hyperemesis gravidarum, and nausea and vomiting with the acquired immunodeficiency syndrome [4].
• The other major success stories of 5-HT research are the discovery of 5-HT1B/D receptor agonists for treating migraine and 5-HT3 receptor antagonists for chemotherapy and radiation-induced emesis [5].

Psychiatry related information on HTR3A

• METHODS: To determine the haplotype block structure in the genomic regions of HTR3A and HTR3B, and to examine whether genetic variations in the region show evidence of association with schizophrenia and affective disorder in the Japanese, we performed haplotype-based case-control analysis using 29 polymorphisms [6].
• Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome [7].
• These findings show that the C178T(Pro16Ser) variant in HTR3A may represent a functional variant and affect the susceptibility to bipolar disorder [8].
• On the other hand, 5-HT3- and 5-HT2C-receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types [9].
• BACKGROUND: 5-hydroxytryptamine-3 (5-HT3) receptor antagonists inhibit gastric phase-3 motor activity in the dog [10].

High impact information on HTR3A

• The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) mediates rapid excitatory responses through ligand-gated channels (5-HT3 receptors) [11].
• Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus [11].
• Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3 [12].
• Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT1D and 5-HT3 receptor agents [13].
• The fast-acting ligand-gated ion channels (LGICs) constitute a group that encompasses nicotinic ACh, 5-HT3, GABAA and glycine receptors [14].

Chemical compound and disease context of HTR3A

• These 5-HT3- and 5-HT2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders [9].
• Antagonism of 5-HT3 receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT3 receptors excite DVN and NTS neurones by a glutamate-dependent mechanism [15].
• Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission [16].
• CONCLUSIONS: Selective antagonism of 5-HT3 receptors suppresses the gastric component of phase-3 motor activity and simultaneously suppresses plasma motilin peaks [10].
• Interactions between dopamine and 5-HT3 receptors suggest new treatments for psychosis and drug addiction [17].

Biological context of HTR3A

• RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples [6].
• BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry [6].
• CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese [6].
• A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala [18].
• Association analysis showed similar allele and genotype distributions among clozapine responders and nonresponders.These results make unlikely the possibility that 5-HT3A and 5-HT3B receptor genes underlie variation in clinical response to clozapine [19].

Anatomical context of HTR3A

• CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system [20].
• Ciliary body, choroid, and conjunctiva were most enriched in 5HT3 receptor mRNA, with relatively lower levels in the iris [21].
• Based on co-labeling with the pan-neuronal marker HuC/D we conclude that submucous nerve cells potentially express heteromeric 5-HT3A/B receptors [22].
• Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors [22].
• However, preapplication of phalloidin, which stabilizes the actin polymerization, significantly inhibited PMA potentiation of 5-HT-activated responses in both N1E-115 cells and oocytes expressing 5-HT3A receptors [2].

Associations of HTR3A with chemical compounds

• A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women [23].
• Paradoxically, from the results of studies performed on the closely related nicotinic acetylcholine receptor, the channel-lining M2 domain of the 5-HT3A subunit is predicted to enhance cation conduction, whereas that of the 5-HT3B subunit would not [24].
• 5-HT3 (5-hydroxytryptamine type 3) receptors are cation-selective ion channels of the Cys-loop transmitter-gated ion channel superfamily [24].
• Replacement of three arginine residues (R432, R436 and R440) unique to the HA stretch of the 5-HT3A subunit with the aligned residues (Q395, D399 and A403) of the 5-HT3B subunit increased the single-channel conductance 28-fold [24].
• The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022-0.042), and more significantly in paroxetine-treated patients (p = 0.002-0.042) [25].

Regulatory relationships of HTR3A

• Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans [26].
• The present study was undertaken in order to establish the possible involvement of 5-HT3 serotonergic receptors in the control of basal and/or hypoglycemia-stimulated arginine vasopressin (AVP) and/or oxytocin (OT) secretion [27].
• The 5-HT3-receptor antagonist ondansetron inhibited the plasma CGRP and adrenalin response to central hypovolaemia without influencing cardiovascular tolerance [28].
• Using a saporin-substance P conjugate to produce site-specific neuronal ablation, we demonstrate that NK1-R expressing cells in the superficial dorsal horn are crucial for the generation of LTP-like changes in neuronal excitability in deep dorsal horn neurons and this is modulated by descending 5HT3-R-mediated facilitatory controls [29].
• In conclusion, neither 5-HT3 nor 5-HT4 receptors tonically regulate ferret gut motility except that 5-HT3 receptors have a key role in the occurrence of migrating motor complex specifically in the stomach [30].

Other interactions of HTR3A

• Serotonin receptor type 3 is a ligand-gated channel encoded by 2 different subunit genes, HTR3A and HTR3B [23].
• We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions [25].
• The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear [31].
• Moreover, hric3 totally abolished currents evoked by 5-HT3 serotonin receptors, whereas it barely modified alpha1 glycine receptor currents [32].
• The gene structure of the human 5-HT3A receptor gene was analyzed by exon to exon polymerase chain reaction and subsequent sequencing [33].

Analytical, diagnostic and therapeutic context of HTR3A

• Transplantation of this signal (CRAR) into the homologous region of 5-HT3A results in the ER retention of this subunit until rescued by co-assembly with wild-type 5-HT3A [34].
• In addition, using a specific antibody directed to the extracellular N-terminal domain of the 5-HT3A receptor, treatment with the PKC activator, 4 beta-phorbol 12-myristate 13-acetate (PMA), significantly increased surface immunofluorescence [2].
• In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart [35].
• With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum [35].
• METHODS: We included 242 cancer patients at their first day of chemotherapy to investigate the influence of genetic polymorphisms of the 5-HT3A receptor gene on the intensity of nausea and vomiting which was documented using standardized interviews and visual analog scales [3].

References