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

我们研究M_2和M_3亚型M_2和M_3受体在胆碱能神经-膀胱平滑肌传递中的作用，旨在为开发治疗膀胱过度活动症的有效药物提供策略。这些结果表明，不仅M_3亚型，而且M_2亚型也直接产生膀胱收缩，膜去极化和随后的电压门控钙通道开放导致的钙内流是启动M_2和M_3介导的收缩的关键。鉴于过度活动型膀胱M2受体密度增加，M_2受体亚型可能成为治疗过度活动型膀胱炎的潜在靶点。我们还在膀胱平滑肌中发现了非选择性阳离子通道，它负责膜的去极化，其特性与已知的肠平滑肌阳离子通道略有不同。此外，我们还发现，在膀胱条标本中，由M受体刺激产生的膜去极化和动作电位放电频率的增加比在单细胞标本中观察到的相对较差，这表明可能存在一种保护膀胱组织免受M受体刺激引起的过度兴奋的机制。因此，这种保护机制的紊乱可能会导致膀胱过度活动的产生。

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.