Two opposite signal transducing mechanisms regulate a G-protein-coupled guanylyl cyclase
Two opposite signal transducing mechanisms regulate a G-protein-coupled guanylyl cyclase
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DOI：
10.1006/abbi.1997.0469
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发表时间：
1998-02-01
影响因子：
3.9
通讯作者：
de Alfonzo, RG
中科院分区：
文献类型：
--
作者：
Alfonzo, MJ;de Becemberg, IL;de Alfonzo, RG
膜结合鸟苷酸环化酶（GC）受毒蕈碱受体（mAChR）调节，氨甲酰胆碱（CC）诱导对GC活性的“双重”生物学反应，因此，在0.1 nM时观察到激活，在1 nM CC时观察到最大反应，然而，在较高激动剂浓度（>100 nM）下，存在GC的激动剂依赖性抑制，此CC双响应受4-DAMP和HDD影响（M-3拮抗剂），其产生CC曲线的右移; 4-DAMP的最大CC剂量反应比HDD更强，AFDX-DS（M-2拮抗剂）增加基础活性并降低激动剂依赖性抑制，CC反应和CC最大剂量反应均不受哌仑西平影响（PZ，M-1拮抗剂），GC活性的激动剂依赖性刺激被4-DAMP抑制，显示出-log IC 50 = 8.4 +/- 0.4，而AFDX 116 DS对这种活性的抑制很差，显示出-log IC 50 = 5.0 +/- 0.2，激动剂非依赖性（基础）GC活性也被4-DAMP以剂量依赖性方式抑制，IC 50 = 8.5 +/- 0.2。（PZ和HDD）不能抑制这种基础GC，百日咳毒素处理产生对GC的激动剂依赖性抑制的完全阻断，同时完全表达膜结合GC的激动剂依赖性活化，这些结果表明，毒蕈碱类药物通过两条相反的信号通路调节膜结合GC;一种涉及通过与PTX不敏感的G蛋白偶联的M-3 mAchR激活GC，而GC抑制是通过PTX敏感的G（i/o）蛋白介导的，该蛋白可能与M-2 mAChR偶联。(C)北京：科学出版社.
Membrane-bound guanylyl cyclase (GC) is regulated by muscarinic receptors (mAChRs), Carbamylcholine (CC) induces a "dual" biological response on GC activity, Thus, an activation is observed at 0.1 nM and a maximal response at 1 nM CC, However, at higher agonist concentration (>100 nM), there is an agonist-dependent inhibition of GC, This CC dual response is affected by 4-DAMP and HDD (M-3 antagonists), which produce a right-shift of the CC curve; the maximal CC dose response with 4-DAMP is more potent than that with HDD, Moreover, AFDX-DS (an M-2 antagonist) increases basal activity and decreases the agonist-dependent inhibition, Neither the CC response nor the CC maximal dose responses are affected by pirenzepine (PZ, M-1 antagonist), The agonist-dependent stimulation of GC activity is inhibited by 4-DAMP showing a -log IC50 = 8.4 +/- 0.4, while AFDX116 DS poorly inhibits such activity with a -log IC50 = 5.0 +/- 0.2, The agonist-independent (basal) GC activity also was inhibited by 4-DAMP, in a dose-dependent manner, with an IC50 = 8.5 +/- 0.2, Nonetheless, other muscarinic antagonists (PZ and HDD) were not able to inhibit this basal GC, Pertussis toxin treatment produces a complete blockade of the agonist-dependent inhibition of GC with a full expression of the agonist-dependent activation of membrane-bound GC, These results indicate that membrane-bound GC is regulated by muscarinic agents through two opposite signaling pathways; one involves the activation of GC via an M-3 mAchR coupled to a PTX-insensitive G protein, while the GC inhibition is mediated through a PTX-sensitive G(i/o) protein possibly coupled to an M-2 mAChR. (C) 1998 Academic Press.