The roles of muscarinic receptor subtypes in the bladder contractions and the pathogenesis of overactive bladder

毒蕈碱受体亚型在膀胱收缩中的作用和膀胱过度活动症的发病机制

• 批准号: 17580253
• 负责人: UNNO Toshihiro
• 金额: $ 2.3万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17580253/
• 关键词: Muscarinic receptor; Subtype; Knockout mice; Bladder smooth muscle; Overactive bladder; Contractile response; Membrane potential response; Cationic channel

We have studied the functional roles of M_2 and M_3 subtypes of muscarinic receptors in the cholinergic nerve-bladder smooth muscle transmission, aiming to propose the strategy for development of effective drugs treating for the overactive bladder. The present results suggest that not only M_3 subtype, but also M_2 subtype directly produces bladder contractions and that membrane depolarization and subsequent Ca^<2+> influx due to the opening of voltage-gated Ca^<2+> channels are crucial for initiating both the M_2- and M_3-mediated contractions. Considering the fact that the density of M_2 receptors are increased in overactive bladder, M_2 subtype of muscarinic receptor may be a potential target for the treatment of overactive bladder. We also identified nonselective cation channels in bladder smooth muscles, which is responsible for the membrane depolarization and whose properties are somewhat different from those for well documented cation channels in intestinal smooth muscles. Furthermore, we revealed that the membrane depolarization and increased frequency of action potential discharges produced by muscarinic receptor stimulation in bladder strip preparations are relatively very poor than that observed in single cell preparation, suggesting that a mechanism by which the bladder tissue is protected from over-excitation upon muscarinic receptor stimulation may exist. Therefore, it is possible that disturbance of such protective mechanisms may lead to the generation of overactive bladder.

我们研究了毒蕈碱受体M_2和M_3亚型在胆碱能神经-膀胱平滑肌传递中的功能作用，旨在为开发治疗膀胱过度活动症的有效药物提出策略。目前的结果表明，不仅M_3亚型，而且M_2亚型都直接产生膀胱收缩，并且由于电压门控Ca ^ 2+ 通道的开放而引起的膜去极化和随后的Ca ^ 2+ 流入对于启动M_2和M_3介导的收缩至关重要。考虑到膀胱过度活动症患者M_2受体密度增加，毒蕈碱受体M_2亚型可能是膀胱过度活动症治疗的潜在靶点。我们还发现了膀胱平滑肌中的非选择性阳离子通道，它负责膜去极化，其特性与肠道平滑肌中已充分记录的阳离子通道的特性有些不同。此外，我们发现，膀胱条带制剂中毒蕈碱受体刺激产生的膜去极化和动作电位放电频率的增加比单细胞制剂中观察到的要差，这表明可能存在保护膀胱组织免受毒蕈碱受体刺激过度兴奋的机制。因此，这种保护机制的紊乱可能导致膀胱过度活动症的发生。

项目成果

Characterization of muscarinic receptor-mediated cationic currents in longitudinal smooth muscle cells of mouse small intestine

• DOI: 10.1254/jphs.fp0050973
• 发表时间: 2006-03-01
• 期刊: JOURNAL OF PHARMACOLOGICAL SCIENCES
• 影响因子: 3.5
• 作者: Sakamoto, T;Unno, T;Komori, S
• 通讯作者: Komori, S

Three distinct muscarinic signaling pathways for cationic channel activation in mouse gut smooth muscle cells.

小鼠肠道平滑肌细胞中阳离子通道激活的三种不同的毒蕈碱信号通路。

• 发表时间: 2007
• 期刊: Journal of Physiology (印刷中)
• 作者: Al-Mamun;M.;C. Ito;A. Sato and H. Sano;Etsuko Kasuya;Etsuko Kasuya et al.;Etsuko Kasuya et al.;粕谷 悦子;T.Sakamoto et al.
• 通讯作者: T.Sakamoto et al.

Muscarinic cationic current in gastrointestinal smooth muscles: signal transduction and role in contraction

• DOI: 10.1111/j.1474-8673.2006.00366.x
• 发表时间: 2006-07-01
• 期刊: Autonomic & Autacoid Pharmacology
• 作者: Unno, T.;Matsuyama, H.;Komori, S.
• 通讯作者: Komori, S.

Roles of M2 and M3 muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice

• DOI: 10.1038/sj.bjp.0706955
• 发表时间: 2006-12-01
• 期刊: BRITISH JOURNAL OF PHARMACOLOGY
• 影响因子: 7.3
• 作者: Unno, T.;Matsuyama, H.;Komori, S.
• 通讯作者: Komori, S.