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-肾上腺胶体受体（AR）的密码子64中的遗漏突变发生在某些频率中。由于β_3-ar的激活会导致逆肌的放松，因此我们假设这种突变可能与特发性过度活跃的膀胱（OAB）有关，从而导致迫使失禁。因此，本研究是为了研究上述可能性的。我们表明，α__<1a>，α__<1b>，α__<1d>，α_<1d>，β_1和β_2-ar的mRNA以低水平表达，而β_3-AR是人类bladedererser的β_3-AR（大约94％的子类型）。这一主要的β_3-AR在尿液储存过程中在膀胱放松中起着至关重要的作用。我们还研究了通过抑制肌肉中β_3-ar放松的机制。我们的结果表明，除了依赖营地的途径外，BKCA通道还参与了β_3-ar激动剂诱导的放松在预缩的预扣抑制剂肌肉中的放松。该研究使用CHO-K1细胞表达人β_3-ar及其突变体β_3AR的cho-k1细胞，表明在野外类型和突变的特征中没有显着差异，这些野生型和突变的特征是在野外构造的范围，这些野生型和突变的特征是这些野外的特征，这些野生构成的特征是这些野外的特征，这些特征是这些野生型和突变的差异，这些是在野外构造和突变的特征，这些特征是在这些范围内的构造，以致于这些差异，这些阶段的特性是在野外的特征，这些差异是这些差异。在天前，在大规模临床研究中，我们从100例特发性OAB和101名非OAB对照量的患者那里获得了头发根本样品。我们发现，OAB患者的β_3-AR基因突变的总频率为47％，在非OBAB对照中的突变频率高得多。这些结果为我们的假设提供了支持，即由于其基因突变引起的β_3-AR功能障碍可能是造成OAB症状的原因。这，β_3-AR多态性可用作OAB的遗传标记。