Tanaka Yoshio, Yamashita Yoko, Yamaki Fumiko, Horinouchi Takahiro, Shigenobu Koki, Koike Katsuo
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Miyama 2-2-1, Chiba 274-8510, Funabashi-City, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Nov;368(5):437-41. doi: 10.1007/s00210-003-0809-1. Epub 2003 Oct 3.
Cyclic AMP is a key molecule in the regulation of airway smooth muscle tone. Increased cyclic AMP leads to relaxation of this smooth muscle and its inhibition results in the muscle contraction. A constitutive role for cyclic AMP in the contraction and relaxation of airway muscle is supported by the observations that direct activators of adenylyl cyclase, such as forskolin and membrane-permeable cyclic AMP analogues, relax this smooth muscle potently. This traditional view of the role for cyclic AMP is the basis for the idea that relaxation of airway smooth muscle mediated through adenylyl cyclase-linked, G(s)-coupled receptors, including the beta(2)-adrenoceptor, is achieved mainly by the elevation of cyclic AMP content [cyclic AMP-dependent mechanism(s)]. However, recent pharmacological and biochemical evidence raises a fundamental question concerning the role of cyclic AMP; can G(s)-coupled receptor-mediated relaxation of tracheal smooth muscle be attributed exclusively to cyclic AMP-dependent mechanism(s)? In the present study, we show that cholera toxin (CTX, 5 microg/ml), an activator of the heterotrimeric guanine-nucleotide-binding protein G(s), relaxes guinea-pig tracheal smooth muscle. CTX also elevates tissue cyclic AMP content by about 30-fold and this is practically abolished by an adenylyl cyclase inhibitor, SQ 22,536 (100 microM). However, unexpectedly, the relaxant response to CTX is not affected by SQ 22,536. These results firstly show that activation of G(s) is able to produce a relaxation in tracheal smooth muscle independently of the elevation of cyclic AMP. G(s)-triggered, cyclic AMP-unrelated cellular mechanism(s) seem(s) to play a substantial role in smooth muscle relaxation mediated through adenylyl cyclase-linked receptors. This mechanism may account in part for the cyclic AMP-independent relaxant response of tracheal smooth muscle.
环磷酸腺苷（cAMP）是调节气道平滑肌张力的关键分子。cAMP增加会导致该平滑肌松弛，而其受抑制则会导致肌肉收缩。腺苷酸环化酶的直接激活剂，如福斯可林和可透过细胞膜的cAMP类似物，能有效松弛这种平滑肌，这一观察结果支持了cAMP在气道肌肉收缩和松弛中起组成性作用的观点。cAMP作用的这种传统观点是以下观点的基础，即通过腺苷酸环化酶连接的、G(s)偶联受体（包括β2肾上腺素能受体）介导的气道平滑肌松弛主要是通过提高cAMP含量实现的[依赖cAMP的机制]。然而，最近的药理学和生物化学证据提出了一个关于cAMP作用的基本问题；G(s)偶联受体介导的气管平滑肌松弛是否完全归因于依赖cAMP的机制？在本研究中，我们表明霍乱毒素（CTX，5微克/毫升），一种异三聚体鸟嘌呤核苷酸结合蛋白G(s)的激活剂，可松弛豚鼠气管平滑肌。CTX还可使组织cAMP含量升高约30倍，而腺苷酸环化酶抑制剂SQ 22536（100微摩尔）几乎可消除这种升高。然而，出乎意料的是，对CTX的松弛反应不受SQ 22536的影响。这些结果首先表明，G(s)的激活能够在不依赖cAMP升高的情况下使气管平滑肌产生松弛。G(s)触发的、与cAMP无关的细胞机制似乎在通过腺苷酸环化酶连接受体介导的平滑肌松弛中起重要作用。这种机制可能部分解释了气管平滑肌不依赖cAMP的松弛反应。
