Lubiprostone targets prostanoid EP4 receptors in ovine airways
Lubiprostone targets prostanoid EP4 receptors in ovine airways
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DOI：
10.1111/j.1476-5381.2010.01058.x
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发表时间：
2011-01-01
影响因子：
7.3
通讯作者：
Cuthbert, A. W.
中科院分区：
文献类型：
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作者：
Cuthbert, A. W.
背景和技术鲁比前列酮是一种前列腺素E-1衍生物，据报道可激活位于许多转运上皮细胞顶端膜中的ClC-2氯离子通道。上皮细胞中功能性CFTR氯离子通道的缺乏是遗传性疾病囊性纤维化的原因，因此，可以独立于CFTR运行的替代通道是令人感兴趣的。本研究探索了鲁比前列酮在气道上皮中的靶受体。实验方法所有实验均在绵羊腹侧气管上皮上进行。使用光学方法，上皮被用于测量来自顶端表面的阴离子分泌，作为短路电流或作为来自个体气道粘膜下腺体的液体分泌。关键词EP 4拮抗剂L-161982和GW 627368抑制对鲁比前列酮的短路电流反应，而EP 1，2和3受体拮抗剂没有作用。同样，L-161982抑制鲁比前列酮诱导的气道粘膜下腺体分泌。L-161982与鲁比前列酮有效竞争，K-d值为0.058 μ M，接近其与人EP 4受体结合的值（0.024 μ M）。选择性EP 4激动剂L-902688和鲁比前列酮的表现与EP 4受体拮抗剂相似。实验结果与H89，蛋白激酶A抑制剂，是一致的鲁比前列酮通过G（S）-蛋白偶联EP 4受体/cAMP cascades. CONCLUSION和IMPLICATIONSLUbiprostone诱导的短路电流和粘膜下腺分泌抑制选择性EP 4受体拮抗剂。结果表明，鲁比前列酮激活EP 4受体触发CFTR激活和分泌反应所必需的cAMP产生，这是CF组织中排除的一种可能性。
BACKGROUND AND PURPOSELubiprostone, a prostaglandin E-1 derivative, is reported to activate ClC-2 chloride channels located in the apical membranes of a number of transporting epithelia. Lack of functioning CFTR chloride channels in epithelia is responsible for the genetic disease cystic fibrosis, therefore, surrogate channels that can operate independently of CFTR are of interest. This study explores the target receptor(s) for lubiprostone in airway epithelium.EXPERIMENTAL APPROACHAll experiments were performed on the ventral tracheal epithelium of sheep. Epithelia were used to measure anion secretion from the apical surface as short circuit current or as fluid secretion from individual airway submucosal glands, using an optical method.KEY RESULTSThe EP4 antagonists L-161982 and GW627368 inhibited short circuit current responses to lubiprostone, while EP1,2&3 receptor antagonists were without effect. Similarly, lubiprostone induced secretion in airway submucosal glands was inhibited by L-161982. L-161982 effectively competed with lubiprostone with a K-d value of 0.058 mu M, close to its value for binding to human EP4 receptors (0.024 mu M). The selective EP4 agonist L-902688 and lubiprostone behaved similarly with respect to EP4 receptor antagonists. Results of experiments with H89, a protein kinase A inhibitor, were consistent with lubiprostone acting through a G(s)-protein coupled EP4 receptor/cAMP cascade.CONCLUSIONS AND IMPLICATIONSLubiprostone-induced short-circuit currents and submucosal gland secretions were inhibited by selective EP4 receptor antagonists. The results suggest EP4 receptor activation by lubiprostone triggers cAMP production necessary for CFTR activation and the secretory responses, a possibility precluded in CF tissues.