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

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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.