Flowchart: Preparation: Htr4        




Text Box: 5-HT4                                  



Text Box: HTR4 Text Box: HTR2B









Am J Med Genet B Neuropsychiatr Genet. 2003 Aug 15;121(1):7-13.

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Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia.

Suzuki T, Iwata N, Kitamura Y, Kitajima T, Yamanouchi Y, Ikeda M, Nishiyama T, Kamatani N, Ozaki N.

Department of Psychiatry,
Fujita Health University, Toyoake, Aichi, Japan.

The serotonin 5-HT(4) receptor (5-HT(4)) is implicated in cognitive function, of which impairment is hypothesized as one of the core disturbances of schizophrenia. Linkage analysis shows that 5q33.2, in which HTR4 is located, is schizophrenia-susceptibility loci. We therefore hypothesized that variation in the 5-HT(4) receptor gene (HTR4) modifies genetic susceptibility to schizophrenia. HTR4 coding regions and introns that include the branch sites of HTR4 were investigated in 96 unrelated Japanese schizophrenics using denaturing high-performance liquid chromatography analysis. One silent single nucleotide polymorphism (SNP) within the coding region and six intronic SNPs were detected. 353 + 6G > A was located in the branch site that could be effect to RNA splicing. None of the four SNPs, in which rare-allele frequencies were more than 10% was associated with 189 schizophrenics, in comparison to 299 controls. However, a highly significant association between schizophrenia and haplotype A-T (OR = 0.13 [0.03-0.58]) was detected. These findings suggest that haplotype A-T itself may inhibit the occurrence of schizophrenia, or that another susceptible genetic variants may exist within linkage disequilibrium. Copyright 2003 Wiley-Liss, Inc.

PMID: 12898568 [PubMed - indexed for MEDLINE]

Mol Psychiatry. 2002;7(9):954-61.

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Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees.

Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T.

Department of Medical Genetics, Institute of Basic Medical Sciences,
University of Tsukuba, Tsukuba, Ibaraki, Japan.

Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder.

PMID: 12399948 [PubMed - indexed for MEDLINE]


Eur Urol. 2005 Jun;47(6):895-900. Epub 2005 Mar 3.

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Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines.

Dizeyi N, Bjartell A, Hedlund P, Tasken KA, Gadaleanu V, Abrahamsson PA.

Department of Urology,
Malmo University Hospital, Lund University; SE-205 02 Malmo, Sweden. nishtman.dizeyi@kir.mas.lu.se

OBJECTIVES: Overexpression of receptors to neuroendocrine (NE) cell products has been suggested to contribute to development of hormone-refractory prostate cancer (HRPC). In this study, we evaluated the expression of 5-HTR2B and 5-HTR4 in HRPC, and the effects of their antagonist on PC cell line growth. METHODS: Proteins and mRNA expression was determined by immunohistochemistry, western blot and RT-PCR. Growth inhibition of PC cell lines was determined in vitro using ELISA-BrdU proliferation assay and cell cycle was evaluated by flow cytometry. RESULTS: Immunostaining of 5-HTR2B was observed in low-grade and high-grade tumours, PIN and BPH cells, and in vascular endothelial cells, whereas 5-HTR4 was found predominantly in high-grade tumours. This result was confirmed by western blot analysis. At the mRNA level, 5-HTR4 mRNA was expressed in DU145 and LNCaP cells. Antagonists to both receptor subtypes inhibited proliferation of PC cells in a dose-dependent manner. CONCLUSIONS: The present result indicate that 5-HTRs are present at various tumour stages and that antagonists to these receptors can inhibit the proliferative activity of androgen-independent PC cell lines.

PMID: 15925089 [PubMed - indexed for MEDLINE]