The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells.
The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells.
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Cdc42 抑制剂 secramine B 可防止肠上皮细胞中 cAMP 诱导的 K 电导。
DOI：
10.1016/j.bcp.2006.03.011
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发表时间：
2006
影响因子：
5.8
通讯作者：
Lencer,WayneI
中科院分区：
文献类型：
--
作者：
Pelish,HenryE;Ciesla,William;Tanaka,Nori;Reddy,Krishna;Shair,MatthewD;Kirchhausen,Tomas;Lencer,WayneI
环腺苷酸（cAMP）和钙依赖性激动剂通过协调激活粘膜上皮细胞中不同的顶侧和基底侧膜通道和离子转运蛋白刺激氯分泌。囊性纤维化和霍乱弧菌感染时会出现跨粘膜表面氯离子转运调节缺陷，并可能危及生命。在这里，我们报告，secramine B，一个小分子，抑制激活的Rho GTdR Cdc 42，减少cAMP刺激的氯化物分泌在人肠细胞系T84。Secramine B干扰cAMP门控和Ba 2+敏感的K+通道，推测为KCNQ 1/KCNE 3。该通道是维持膜电位所必需的，膜电位维持氯化物分泌。相反，Secramine B不影响Ca 2+介导的氯分泌途径，这需要一个独立的K+通道活性的cAMP。Pirl 1是另一种在结构上与Secramine B无关的小分子，也在体外抑制Cdc 42活化，类似地抑制cAMP依赖性但不抑制Ca 2+依赖性氯分泌。这些结果表明，Rho GTPases可能参与氯分泌反应的调节，并确定secramine B是肠上皮细胞cAMP依赖性K+电导的抑制剂。
Cyclic AMP- (cAMP) and calcium-dependent agonists stimulate chloride secretion through the coordinated activation of distinct apical and basolateral membrane channels and ion transporters in mucosal epithelial cells. Defects in the regulation of Cl−transport across mucosal surfaces occur with cystic fibrosis and V. cholerae infection and can be life threatening. Here we report that secramine B, a small molecule that inhibits activation of the Rho GTPase Cdc42, reduced cAMP-stimulated chloride secretion in the human intestinal cell line T84. Secramine B interfered with a cAMP-gated and Ba2+-sensitive K+channel, presumably KCNQ1/KCNE3. This channel is required to maintain the membrane potential that sustains chloride secretion. In contrast, secramine B did not affect the Ca2+-mediated chloride secretion pathway, which requires a separate K+channel activity from that of cAMP. Pirl1, another small molecule structurally unrelated to secramine B that also inhibits Cdc42 activation in vitro, similarly inhibited cAMP-dependent but not Ca2+-dependent chloride secretion. These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K+conductance in intestinal epithelial cells.