Agonist-Specific Compartmentation of cGMP Action in Myometrium
Agonist-Specific Compartmentation of cGMP Action in Myometrium
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DOI：
10.1124/jpet.110.171934
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发表时间：
2010-10-10
影响因子：
3.5
通讯作者：
Tichenor, Stephen D.
中科院分区：
文献类型：
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作者：
Buxton, Iain L. O.;Milton, Deanna;Tichenor, Stephen D.
一氧化氮以一种不依赖环鸟苷酸（cGMP）的方式使子宫肌层松弛。尽管cGMP能激活其同源激酶，但这对于一氧化氮的抑制作用并非必需。因此，一氧化氮介导的cGMP升高所作用的底物与在其他平滑肌中的情况不同。为了进一步了解环鸟苷酸对子宫肌松弛的调节作用，我们研究了肽介导的环鸟苷酸作用在豚鼠子宫肌层中的情况。我们对颗粒性鸟苷酸环化酶激活剂尿鸟苷素及其受体C型颗粒性鸟苷酸环化酶的作用进行了功能和生化研究，以探讨在细胞膜信号区域起作用的cGMP升高与细胞非膜区域之间的关系。尿鸟苷素仅在妊娠子宫肌层中以剂量依赖的方式松弛催产素诱导的收缩。尿鸟苷素刺激后的松弛和cGMP积累都被假定的C型颗粒性鸟苷酸环化酶抑制剂2 - 氯 - ATP和靛红（1H - 吲哚 - 2,3 - 二酮）阻断，但不被可溶性鸟苷酸环化酶抑制剂1H - [1,2,4]恶二唑并[4,3 - A]喹喔啉 - 1 - 酮（ODQ）阻断。尿鸟苷素仅在妊娠子宫肌层中刺激cGMP积累。小窝蛋白 - 1的表达在妊娠接近足月时增加。在含有小窝蛋白 - 1的膜区域，尿鸟苷素（而非一氧化氮供体）导致cGMP升高，且这种升高对ODQ不敏感。C型颗粒性鸟苷酸环化酶在妊娠子宫肌层中表达，并且检测到原尿鸟苷素。我们得出结论，存在一种尿鸟苷素 - 颗粒性环化酶 - cGMP松弛途径，并且cGMP在子宫肌层中是分区存在的。激动剂介导的对cGMP松弛的选择性在理解平滑肌中的信号转导方面具有重要的药理学意义。
Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles. To further understand the regulation of relaxation of uterine muscle by cGMP, we have studied the actions of peptide-mediated cGMP action in guinea pig myometrium. We used both functional and biochemical studies of the action of the particulate guanylyl cyclase activator uroguanylin and its receptor, particulate guanylyl cyclase type C, to address the relationship between cGMP elevation acting in the membrane signaling domain to that of the nonmembrane region of the cell. Uroguanylin relaxed oxytocin-induced contractions in a dose-dependent fashion only in pregnant myometrium. Both relaxation and cGMP accumulation after uroguanylin stimulation were blocked by the putative particulate guanylyl cyclase type C inhibitors 2-chloro-ATP and isatin (1H-indole-2,3-dione), but not by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one (ODQ). Uroguanylin stimulated cGMP accumulation only in the pregnant myometrium. Caveolin-1 expression increased in pregnancy toward term. In the caveolin-1-containing membrane domain, uroguanylin, but not the nitric-oxide donor, led to the elevation of cGMP that was insensitive to ODQ. Particulate guanylyl cyclase C was expressed and prouroguanylin was detected in pregnant myometrium. We conclude that a uroguanylin-particulate cyclase-cGMP relaxation pathway is present and cGMP is compartmented in myometrium. The agonist-mediated selectivity of relaxation to cGMP is of fundamental pharmacological interest in understanding signal transduction in smooth muscle.