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Beate Niesler - One of the best experts on this subject based on the ideXlab platform.
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the human serotonin type 3 receptor gene HTR3A e allelic variant database
Human Mutation, 2017Co-Authors: Jacopo Celli, Gudrun A Rappold, Beate NieslerAbstract:Serotonin type 3 (5-HT3) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case–control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype–phenotype correlation studies and pharmacogenetic approaches.
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serotonin type 3 receptor genes HTR3A b c d e
Pharmacogenomics, 2008Co-Authors: Beate Niesler, Johannes Kapeller, Christian Hammer, Gudrun A RappoldAbstract:The 5-HT3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT3A–E, which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.
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characterization of the novel human serotonin receptor subunits 5 ht3c 5 ht3d and 5 ht3e
Molecular Pharmacology, 2007Co-Authors: Beate Niesler, Johannes Kapeller, Gudrun A Rappold, Jutta Walstab, Dorothee Moller, Heinz Bonisch, Sandra Combrink, Jens Rietdorf, M Gothert, Michael BrussAbstract:Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT 3 ) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT 3A and 5-HT 3B subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT 3 receptors, which cannot solely be explained on the basis of the 5-HT 3A and 5-HT 3B subunits. After our discovery of further putative 5-HT 3 serotonin receptor-encoding genes, HTR3C , HTR3D , and HTR3E , we investigated whether these novel candidates and the isoform 5-HT 3Ea are able to form functional 5-HT 3 receptor complexes. Using immunofluorescence and immunoprecipitation studies of heterologously expressed proteins, we found that each of the respective candidates coassembles with 5-HT 3A . To investigate whether the novel subunits modulate 5-HT 3 receptor function, we performed radioligand-binding assays and calcium-influx studies in human embryonic kidney 293 cells. Our experiments revealed that the 5-HT 3C ,5-HT 3D , 5-HT 3E , and 5-HT 3Ea subunits alone cannot form functional receptors. Coexpression with 5-HT 3A , however, results in the formation of functional heteromeric complexes with different serotonin efficacies. Potencies of two agonists and antagonists were nearly identical with respect to homomeric 5-HT 3A and heteromeric complexes. However, 5-HT showed increased efficacy with respect to 5-HT 3A/D and 5-HT 3A/E receptors, which is consistent with the increased surface expression compared with 5-HT 3A receptors. In contrast, 5-HT 3A/C and 5-HT 3A/Ea receptors exhibited decreased 5-HT efficacy. These data show for the first time that the novel 5-HT 3 subunits are able to form heteromeric 5-HT 3 receptors, which exhibit quantitatively different functional properties compared with homomeric 5-HT 3A receptors.
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serotonin receptor genes HTR3A and htr3b are not involved in gilles de la tourette syndrome
Psychiatric Genetics, 2005Co-Authors: Beate Niesler, Bernd Frank, Johannes Hebebrand, Gudrun A RappoldAbstract:Serotonin has been implicated in a variety of neuropsychiatric disorders. Serotonergic dysfunction is thought to be involved in the pathophysiology of the Gilles de la Tourette Syndrome (GTS). GTS is characterized by multiple vocal and motoric tics. Among selective, competitive 5-HT(3) receptor antagonists, ondansetron represents a promising drug in GTS treatment. In our study both serotonin receptor subunit genes, HTR3A and HTR3B, were examined for sequence variations in GTS patients. We have analyzed DNA samples from 49 patients by SSCP and dHPLC. In HTR3A, we detected five mutations and in HTR3B the analysis revealed six sequence variants. Statistical analysis rated all variants as probably non-disease-related polymorphisms. Yet a certain effect of the detected variants on the severity of the disease cannot be excluded.
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mutational analysis of serotonin receptor genes HTR3A and htr3b in fibromyalgia patients
Clinical Rheumatology, 2004Co-Authors: Bernd Frank, Beate Niesler, B Bondy, Michael Spath, D Pongratz, M Ackenheil, Christine Fischer, Gudrun A RappoldAbstract:The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous human disorders. Dysfunction of serotonergic neurotransmission is thought to play a major role in the pathophysiology of the fibromyalgia syndrome (FMS) which is characterised by non-restorative sleep and severe pain. In our study, both serotonin receptor subunit genes, HTR3A and HTR3B, have been investigated for sequence variations in FMS patients in order to reveal a possible involvement in the aetiology of FMS. We examined DNA samples from 48 patients with FMS representing sporadic cases by single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (dHPLC) analysis, sequenced samples with conspicuous patterns and performed statistical calculations. HTR3A mutational analysis revealed one novel as well as five known sequence variations. Investigating HTR3B, we detected seven formerly described mutations and one novel sequence variant. Statistical computation rated all variants as probably non-disease-related polymorphisms. Nevertheless, one might speculate about an effect of the respective sequence variants on the severity of the disease. Sequence variants of the serotonin receptor subunit genes HTR3A and HTR3B indicate no obvious significance in the aetiology of fibromyalgia, yet they represent the basis for future studies on their pharmacogenetic relevance.
Gudrun A Rappold - One of the best experts on this subject based on the ideXlab platform.
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the human serotonin type 3 receptor gene HTR3A e allelic variant database
Human Mutation, 2017Co-Authors: Jacopo Celli, Gudrun A Rappold, Beate NieslerAbstract:Serotonin type 3 (5-HT3) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case–control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype–phenotype correlation studies and pharmacogenetic approaches.
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serotonin type 3 receptor genes HTR3A b c d e
Pharmacogenomics, 2008Co-Authors: Beate Niesler, Johannes Kapeller, Christian Hammer, Gudrun A RappoldAbstract:The 5-HT3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT3A–E, which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.
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characterization of the novel human serotonin receptor subunits 5 ht3c 5 ht3d and 5 ht3e
Molecular Pharmacology, 2007Co-Authors: Beate Niesler, Johannes Kapeller, Gudrun A Rappold, Jutta Walstab, Dorothee Moller, Heinz Bonisch, Sandra Combrink, Jens Rietdorf, M Gothert, Michael BrussAbstract:Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT 3 ) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT 3A and 5-HT 3B subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT 3 receptors, which cannot solely be explained on the basis of the 5-HT 3A and 5-HT 3B subunits. After our discovery of further putative 5-HT 3 serotonin receptor-encoding genes, HTR3C , HTR3D , and HTR3E , we investigated whether these novel candidates and the isoform 5-HT 3Ea are able to form functional 5-HT 3 receptor complexes. Using immunofluorescence and immunoprecipitation studies of heterologously expressed proteins, we found that each of the respective candidates coassembles with 5-HT 3A . To investigate whether the novel subunits modulate 5-HT 3 receptor function, we performed radioligand-binding assays and calcium-influx studies in human embryonic kidney 293 cells. Our experiments revealed that the 5-HT 3C ,5-HT 3D , 5-HT 3E , and 5-HT 3Ea subunits alone cannot form functional receptors. Coexpression with 5-HT 3A , however, results in the formation of functional heteromeric complexes with different serotonin efficacies. Potencies of two agonists and antagonists were nearly identical with respect to homomeric 5-HT 3A and heteromeric complexes. However, 5-HT showed increased efficacy with respect to 5-HT 3A/D and 5-HT 3A/E receptors, which is consistent with the increased surface expression compared with 5-HT 3A receptors. In contrast, 5-HT 3A/C and 5-HT 3A/Ea receptors exhibited decreased 5-HT efficacy. These data show for the first time that the novel 5-HT 3 subunits are able to form heteromeric 5-HT 3 receptors, which exhibit quantitatively different functional properties compared with homomeric 5-HT 3A receptors.
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serotonin receptor genes HTR3A and htr3b are not involved in gilles de la tourette syndrome
Psychiatric Genetics, 2005Co-Authors: Beate Niesler, Bernd Frank, Johannes Hebebrand, Gudrun A RappoldAbstract:Serotonin has been implicated in a variety of neuropsychiatric disorders. Serotonergic dysfunction is thought to be involved in the pathophysiology of the Gilles de la Tourette Syndrome (GTS). GTS is characterized by multiple vocal and motoric tics. Among selective, competitive 5-HT(3) receptor antagonists, ondansetron represents a promising drug in GTS treatment. In our study both serotonin receptor subunit genes, HTR3A and HTR3B, were examined for sequence variations in GTS patients. We have analyzed DNA samples from 49 patients by SSCP and dHPLC. In HTR3A, we detected five mutations and in HTR3B the analysis revealed six sequence variants. Statistical analysis rated all variants as probably non-disease-related polymorphisms. Yet a certain effect of the detected variants on the severity of the disease cannot be excluded.
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mutational analysis of serotonin receptor genes HTR3A and htr3b in fibromyalgia patients
Clinical Rheumatology, 2004Co-Authors: Bernd Frank, Beate Niesler, B Bondy, Michael Spath, D Pongratz, M Ackenheil, Christine Fischer, Gudrun A RappoldAbstract:The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous human disorders. Dysfunction of serotonergic neurotransmission is thought to play a major role in the pathophysiology of the fibromyalgia syndrome (FMS) which is characterised by non-restorative sleep and severe pain. In our study, both serotonin receptor subunit genes, HTR3A and HTR3B, have been investigated for sequence variations in FMS patients in order to reveal a possible involvement in the aetiology of FMS. We examined DNA samples from 48 patients with FMS representing sporadic cases by single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (dHPLC) analysis, sequenced samples with conspicuous patterns and performed statistical calculations. HTR3A mutational analysis revealed one novel as well as five known sequence variations. Investigating HTR3B, we detected seven formerly described mutations and one novel sequence variant. Statistical computation rated all variants as probably non-disease-related polymorphisms. Nevertheless, one might speculate about an effect of the respective sequence variants on the severity of the disease. Sequence variants of the serotonin receptor subunit genes HTR3A and HTR3B indicate no obvious significance in the aetiology of fibromyalgia, yet they represent the basis for future studies on their pharmacogenetic relevance.
Johannes Kapeller - One of the best experts on this subject based on the ideXlab platform.
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functional variants of the serotonin receptor type 3a and b gene are associated with eating disorders
Pharmacogenetics and Genomics, 2009Co-Authors: Christian Hammer, Johannes Kapeller, Christine Fischer, Johannes Hebebrand, Max Endele, Anke Hinney, Susann Friedel, Monica Gratacos, Xavier Estivill, Manfred M FichterAbstract:Objective As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT 3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT 3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). Methods Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. Results In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P= 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P=0.034 , odds ratio=2.26). Conclusion Our study provides first evidence for an involvement of 5-HT 3 variants in the aetiopathology of eating disorders in humans.
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first evidence for an association of a functional variant in the microrna 510 target site of the serotonin receptor type 3e gene with diarrhea predominant irritable bowel syndrome
Human Molecular Genetics, 2008Co-Authors: Johannes Kapeller, Lesley A Houghton, Hubert Monnikes, Jutta Walstab, Dorothee Moller, Heinz Bonisch, Barbara Burwinkel, Frank Autschbach, Benjamin Funke, Felix LasitschkaAbstract:Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.
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serotonin type 3 receptor genes HTR3A b c d e
Pharmacogenomics, 2008Co-Authors: Beate Niesler, Johannes Kapeller, Christian Hammer, Gudrun A RappoldAbstract:The 5-HT3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT3A–E, which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.
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characterization of the novel human serotonin receptor subunits 5 ht3c 5 ht3d and 5 ht3e
Molecular Pharmacology, 2007Co-Authors: Beate Niesler, Johannes Kapeller, Gudrun A Rappold, Jutta Walstab, Dorothee Moller, Heinz Bonisch, Sandra Combrink, Jens Rietdorf, M Gothert, Michael BrussAbstract:Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT 3 ) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT 3A and 5-HT 3B subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT 3 receptors, which cannot solely be explained on the basis of the 5-HT 3A and 5-HT 3B subunits. After our discovery of further putative 5-HT 3 serotonin receptor-encoding genes, HTR3C , HTR3D , and HTR3E , we investigated whether these novel candidates and the isoform 5-HT 3Ea are able to form functional 5-HT 3 receptor complexes. Using immunofluorescence and immunoprecipitation studies of heterologously expressed proteins, we found that each of the respective candidates coassembles with 5-HT 3A . To investigate whether the novel subunits modulate 5-HT 3 receptor function, we performed radioligand-binding assays and calcium-influx studies in human embryonic kidney 293 cells. Our experiments revealed that the 5-HT 3C ,5-HT 3D , 5-HT 3E , and 5-HT 3Ea subunits alone cannot form functional receptors. Coexpression with 5-HT 3A , however, results in the formation of functional heteromeric complexes with different serotonin efficacies. Potencies of two agonists and antagonists were nearly identical with respect to homomeric 5-HT 3A and heteromeric complexes. However, 5-HT showed increased efficacy with respect to 5-HT 3A/D and 5-HT 3A/E receptors, which is consistent with the increased surface expression compared with 5-HT 3A receptors. In contrast, 5-HT 3A/C and 5-HT 3A/Ea receptors exhibited decreased 5-HT efficacy. These data show for the first time that the novel 5-HT 3 subunits are able to form heteromeric 5-HT 3 receptors, which exhibit quantitatively different functional properties compared with homomeric 5-HT 3A receptors.
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cloning physical mapping and expression analysis of the human 5 ht3 serotonin receptor like genes htr3c htr3d and htr3e
Gene, 2003Co-Authors: Beate Niesler, Johannes Kapeller, Bernd Frank, Gudrun A RappoldAbstract:For more than 50 years the serotonin system has been the subject of intense research. This has provided an exciting insight and led to the discovery of multiple drugs targeting serotonin receptors, metabolising enzymes and re-uptake sites. During the past few years researchers focussed especially on elucidating the complexity of different physiological actions in the serotonergic network. We have identified two novel human serotonin 5-hydroxytryptamine type 3 receptor-like genes, HTR3D and HTR3E, by performing homology searches using the public human sequence databases and subsequently cloned the full length cDNAs by 5' and 3' rapid amplification of complementary DNA ends. Mapping of HTR3D and HTR3E by hybridisation, polymerase chain reaction and fluorescence in situ hybridisation revealed that both genes together with HTR3C are clustered in a subinterval of less than 100 kb on chromosome 3q27. Comparative expression analysis of all HTR3 genes, namely HTR3A, B, C, D and E showed HTR3D expression to be restricted to kidney, colon and liver and HTR3E expression to colon and intestine, whereas all other genes are widely expressed in many tissues including brain.
James L Kennedy - One of the best experts on this subject based on the ideXlab platform.
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effect of 5ht genes in conferring risk for suicide attempt and suicidal ideation
European Neuropsychopharmacology, 2019Co-Authors: Vincenzo De Luca, James L Kennedy, Eric J Lenze, Charles F Reynolds, Ali Banifatemi, Benoit H MulsantAbstract:Background Major Depressive Disorder (MDD) is a major risk factor for suicide. Familial, adoption, and twin studies suggest that suicide is both genetic and heritable. However, to date, there are no robust genetic predictors of suicide or suicide attempt in MDD. Several serotonin genes have been proposed as candidate genes in suicidal behaviour, including HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2, 5HTT, and MAOA. The findings from candidate gene studies in suicidal behavior are inconsistent. Methods In this study, we genotyped several functional variants of serotonin genes in a well characterized sample of patients with MDD. Results We found that the G allele in the HTTLPR region is associated with a history of suicide attempt (p Discussion This suggests that this rare variant should be analyzed independently from the nearby long/short polymorphism. However, all previous studies on suicide attempt have neglected this rare variant or combined it with the long/short polymorphism. In conclusion, this study suggests that the G allele in the HTTLPR region should be considered as a single marker in the studies of genetic predictors of suicide attempt.
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norepinephrine transporter gene variants and remission from depression with venlafaxine treatment in older adults
American Journal of Psychiatry, 2017Co-Authors: Victoria S Marshe, Arun K Tiwari, Malgorzata Maciukiewicz, Soham Rej, Etienne Sibille, Daniel M Blumberger, Jordan F Karp, Eric J Lenze, Charles F Reynolds, James L KennedyAbstract:Objective:The primary objective of this study was to investigate five putatively functional variants of the norepinephrine transporter (SLC6A2, NET) and serotonin transporter (SLC6A4, SERT) genes and remission in depressed older adults treated with venlafaxine. A secondary objective was to analyze 17 other variants in serotonergic system genes (HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2) potentially involved in the mechanism of action of venlafaxine.Method:The sample included 350 adults age 60 or older with DSM-IV-defined major depressive disorder and a score of at least 15 on the Montgomery-Asberg Depression Rating Scale (MADRS). Participants received protocolized treatment with open-label venlafaxine, up to 300 mg/day for approximately 12 weeks, as part of a three-site clinical trial. Each individual was genotyped for 22 polymorphisms in eight genes, which were tested for association with venlafaxine remission (a MADRS score ≤10) and changes in MADRS score during treatment.Results:After adjusting for multip...
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association study of serotonin 3 receptor subunit gene variants in antipsychotic induced weight gain
Neuropsychobiology, 2016Co-Authors: Arun K Tiwari, Natalie Freeman, Eva J Brandl, Nabilah I Chowdhury, Sajid A. Shaikh, Herbert Y Meltzer, James L Kennedy, Jeffrey A. Lieberman, Daniel J MullerAbstract:Background: Schizophrenia (SCZ) is a chronic severe neuropsychiatric disorder, where pharmacological treatment has been hindered by adverse effects, including antipsychotic-induced weight gain (AIWG) and related complications. Genetic studies have been exploring the appetite regulation and energy homeostasis pathways in AIWG with some promising leads. The serotonin system has been shown to participate in these pathways. Methods: In the current study, we examined single nucleotide polymorphisms across the serotonin receptor genes HTR3A and HTR3B . Prospective weight change was assessed for a total of 149 SCZ patients of European ancestry. Results: We did not find the tested HTR3A or HTR3B gene markers to be associated with AIWG in our sample. Conclusion: Our preliminary findings suggest that these receptors may not play a major role in predicting AIWG.
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are serotonin 3a and 3b receptor genes associated with suicidal behavior in schizophrenia subjects
Neuroscience Letters, 2011Co-Authors: Renan P. Souza, Vincenzo De Luca, James L Kennedy, Mirko ManchiaAbstract:Abstract Suicide is a major contributor to the morbidity and mortality of schizophrenia, accounting for approximately 10% of deaths in these patients. Genetic factors have been reported to modulate the risk for suicide, although the precise mechanism and magnitude of the genetic contribution are unknown. Further, suicide attempters present abnormalities in the serotonergic system. We evaluated whether genetic variants in the serotonin receptors HTR3A (rs897692, rs1150226, rs1176724, rs2276302, rs3737457, rs897687 and rs1176713) and HTR3B (rs3758987, rs10502180, rs11606194, rs17116121, rs1176744, rs17116138, rs2276307, rs3782025 and rs1176761) were susceptibility components for suicidal behavior in 154 Caucasians schizophrenia subjects (20.1% of suicide attempters). In a second step, we compared haplotype and gene–gene interaction approaches because both genes are located in the chromosome 11q23 approximately 28 Kbp apart. We did not observe allelic or genotypic associations. Six haplotypes were nominally significant associated with suicide. Gene–gene interaction using Helix Tree software showed two nominally significant interactions reproduced by haplotype association. Likewise, haplotypes composed by the markers included in the best multidimensional reduction three-locus model were nominally significant. Our results suggest that HTR3A and HTR3B polymorphisms may not play a major role in the susceptibility for suicidal behavior in schizophrenia subjects. Moreover, gene–gene interaction and haplotype association may have consistent results for genes located in the same chromosome.
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Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia.
Pharmacogenetics and Genomics, 2010Co-Authors: Renan P. Souza, Herbert Y Meltzer, Vincenzo De Luca, Jeffrey A. Lieberman, James L KennedyAbstract:Earlier results suggest a minor role of variants in the serotonin 3 receptor (HTR3) subunit genes on antipsychotic treatment outcome of schizophrenia patients. In this study, we further investigated the role of the subunits A and B of the HTR3 receptor using 140 schizophrenia patients taking clozapine for 6 months. We have found significant allelic association of clozapine response with three variants in the HTR3A receptor (rs2276302, rs1062613, rs1150226) although only rs1062613 association remained significant after permutations (permutated P=0.041). Moreover, rs2276302 and rs1062613 have shown nominally significant genotypic association. The two haplotypes composed of rs2276302-rs1062613-rs1150226 were also nominally significant. Taken together, our results suggest that variants in the HTR3A receptor gene can play a role in the treatment outcome of clozapine in schizophrenia patients that are refractory or intolerant of typical antipsychotic therapy. Further studies are necessary to confirm the reported associations.
Christian Hammer - One of the best experts on this subject based on the ideXlab platform.
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replication of functional serotonin receptor type 3a and b variants in bipolar affective disorder a european multicenter study
Translational Psychiatry, 2012Co-Authors: Christian Hammer, Sven Cichon, Thomas W Muhleisen, Britta Haenisch, Franziska Degenhardt, M Mattheisen, Rene Breuer, S H Witt, J StrohmaierAbstract:Serotonin type 3 receptors (5-HT3) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802–0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT3 receptor function in BPAD.
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functional variants of the serotonin receptor type 3a and b gene are associated with eating disorders
Pharmacogenetics and Genomics, 2009Co-Authors: Christian Hammer, Johannes Kapeller, Christine Fischer, Johannes Hebebrand, Max Endele, Anke Hinney, Susann Friedel, Monica Gratacos, Xavier Estivill, Manfred M FichterAbstract:Objective As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT 3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT 3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). Methods Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. Results In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P= 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P=0.034 , odds ratio=2.26). Conclusion Our study provides first evidence for an involvement of 5-HT 3 variants in the aetiopathology of eating disorders in humans.
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serotonin type 3 receptor genes HTR3A b c d e
Pharmacogenomics, 2008Co-Authors: Beate Niesler, Johannes Kapeller, Christian Hammer, Gudrun A RappoldAbstract:The 5-HT3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT3A–E, which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.