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Urinary Incontinence and Mutation of β_3 Adrenoceptor Gene

尿失禁与β_3肾上腺素受体基因突变

基本信息

批准号：
12470335
负责人：
YAMAGUCHI Osamu
金额：
$ 7.04万
依托单位：
Fukushima Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

A miss-sense mutation in codon 64 of the β_3-adrenoceptor(AR) occurs with some frequency. Because activation of the β_3-AR causes a relaxation of detrusor muscle, we hypothesized that this mutation may be involved in idiopathic overactive bladder(OAB), leading to urge incontinence. The present study was therefore undertaken to investigate the above possibility.We showed that the mRNA of α_<1a>,α_<1b>,α_<1d>, β_1 and β_2-AR was expressed at low levels, while β_3-AR was the most highly expressed subtype(approximately 94% of the overall messages) in human bladder. This predominant β_3-AR plays an essential role in relaxation of the bladder during urine storage.We also investigated the mechanisms of relaxation via β_3-AR in detrusor muscle. Our results suggest that in addition to cAMP-dependent pathway, BKca channels are involved in the β_3-AR agonists-induced relaxation in pre-contracted detrusor muscle.The studies, using CHO-K1 cells that express human β_3-AR and its mutant β_3AR, showed that there was no significant difference between wild type and mutation in terms of binding characteristics and cAMP production.However, these findings can not be directly transferred to the in vivo situation.Frinally, in large scale clinical study, we obtained hair root samples from 100 patients with idiopathic OAB and 101 non-OAB control volumteers. We found that the overall frequency of the β_3-AR gene mutation was 47% in the OAB patients, which was much higher than the mutation frequency of 22.8% in non-OAB control. These results provide support for our hypothesis that dysfunction of β_3-AR resulting from its gene mutation may be responsible for developing OAB symptoms. Thus, the β_3-AR polymorphism may be used as a genetic marker for OAB.

β_3-肾上腺素能受体（AR）第64位密码子存在一定频率的错义突变。由于β_3-AR的激活导致逼尿肌松弛，我们推测该突变可能与特发性膀胱过度活动症（OAB）有关，导致急迫性尿失禁。结果表明，α<1a>_<1b>、β<1d>_1和β_2-AR的mRNA在人膀胱组织中均呈低水平表达，而β_3-AR的mRNA表达量最高（约占总信息量的94%）。本研究还探讨了逼尿肌β_3-AR的舒张机制。我们的结果表明，除了cAMP依赖的途径外，BKca通道也参与了β_3-AR激动剂诱导的逼尿肌舒张作用。在大规模临床研究中，我们采集了100例特发性OAB患者和101例非OAB对照者的毛根标本。结果表明，OAB患者β_3-AR基因突变率为47%，明显高于非OAB对照组的22.8%。这些结果支持了β_3-AR基因突变导致的功能障碍可能是OAB症状发生的原因。因此，β_3-AR基因多态性可作为OAB的遗传标记。