Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
J Pharmacol Exp Ther. 2010 Oct;335(1):256-63. doi: 10.1124/jpet.110.171934. Epub 2010 Jul 22.
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.
一氧化氮以 cGMP 非依赖的方式使子宫平滑肌松弛。尽管 cGMP 可激活其同源激酶，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 升高并不享有与其他平滑肌相同的底物。为了进一步了解 cGMP 对子宫肌肉松弛的调节作用，我们研究了肽介导的 cGMP 作用在豚鼠子宫平滑肌中的作用。我们使用颗粒型鸟苷酸环化酶激活剂尿鸟苷素及其受体颗粒型鸟苷酸环化酶 C 的功能和生化研究来解决 cGMP 升高在细胞膜信号域和细胞非膜区域的作用之间的关系。尿鸟苷素以剂量依赖的方式仅在妊娠子宫中使催产素诱导的收缩松弛。尿鸟苷素刺激后的松弛和 cGMP 积累均被假定的颗粒型鸟苷酸环化酶 C 抑制剂 2-氯-ATP 和异吲哚-1,3-二酮（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中刺激 cGMP 积累。妊娠晚期 caveolin-1 的表达增加。在含有 caveolin-1 的膜结构域中，尿鸟苷素而非一氧化氮供体导致对 ODQ 不敏感的 cGMP 升高。颗粒型鸟苷酸环化酶 C 表达并在妊娠子宫中检测到前尿鸟苷素。我们得出结论，存在尿鸟苷素-颗粒型环化酶-cGMP 松弛途径，并且 cGMP 在子宫平滑肌中被分隔。激动剂介导的 cGMP 松弛的选择性对理解平滑肌中的信号转导具有重要的药理学意义。
