Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors
Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors
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DOI：
10.1007/s00210-007-0208-0
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Michel, Martin C.
中科院分区：
文献类型：
--
作者：
Frazier, Elfaridah P.;Peters, Stephan L. M.;Michel, Martin C.
膀胱的正常生理收缩是排尿所必需的，主要由M-3亚型M受体介导，M-2亚型起辅助支持作用。尿液储存所需的膀胱松弛是由β-肾上腺素能受体介导的，在大多数物种中都含有很强的β-受体成分。在排尿周期的储存期，过度刺激收缩或减少逼尿肌的松弛可能会导致膀胱功能障碍，称为膀胱过度活跃。因此，干扰这些受体的信号转导可能是开发治疗膀胱过度活动症药物的可行途径。M-3受体的典型信号通路是激活磷脂酶C(PLC)，该通路在膀胱中也被激活。然而，PLC显然只对膀胱收缩起到很小的作用。相反，毒扁豆碱受体介导的膀胱收缩涉及电压操纵的钙通道和Rho激酶。β-肾上腺素能受体的典型信号通路是腺酰环化酶激活，随后形成cAMP。然而，cAMP显然只对β-肾上腺素能受体介导的膀胱松弛起到很小的作用。BKCa通道可能在β-肾上腺素能受体介导的膀胱松弛中发挥更大作用。我们的结论是，除了M受体拮抗剂和β-肾上腺素能受体激动剂外，Rho激酶的抑制剂和BKCa通道的激活剂可能有治疗膀胱过度活动的潜力。
The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M-3 subtype, with the M-2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by beta-adrenoceptors, in most species involving a strong beta(3)-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M-3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of beta-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.