Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon
Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon
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DOI：
10.1016/j.steroids.2011.04.016
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发表时间：
2011-08-01
期刊：
影响因子：
2.7
通讯作者：
Harvey, Brian J.
中科院分区：
文献类型：
--
作者：
Alzamora, Rodrigo;O'Mahony, Fiona;Harvey, Brian J.
分泌过量的氯离子是分泌性腹泻的驱动力。17β-雌二醇可通过非基因组途径抑制大鼠远端结肠的氯离子分泌。在分泌性腹泻的动物模型中，我们研究了17β-雌二醇是否抑制氯离子的分泌，以及相关的下游效应因子。采用电流-电压钳技术研究17β-雌二醇对霍乱毒素和耐热肠毒素诱导的大鼠结肠粘膜膜氯离子分泌的影响。分别用两性霉素B或制霉菌素选择性透入根尖或基底侧膜分离基底侧通道和心尖氯通道活动。17β-雌二醇呈剂量依赖性抑制两种毒素的分泌反应，IC50值约为1 nM。这种影响是女性特有的，在男性组织中没有观察到抑制作用。17β-雌二醇对纯抗雌激素ICI182,720不敏感。17β-雌二醇作用于肠毒素诱导的第二信使(cAMP和cGMP)的下游，但依赖于PKCS的激活。在制霉菌素通透性的组织中，17β-雌二醇处理不影响心尖氯电流，而底侧电流则被激素显著抑制。该电流对特异性KCNQ1通道抑制剂色满酚293B和HMR-1556敏感。综上所述，17β-雌二醇通过抑制KCNQ1底侧通道的PKCS依赖机制抑制肠毒素诱导的氯离子分泌。这些数据阐明了17β-雌二醇抑制肠毒素诱导的肠上皮细胞氯离子分泌的机制，这可能与腹泻疾病的治疗有关。(C)2011 Elsevier Inc.保留所有权利。
Excessive Cl- secretion is the driving force for secretory diarrhea. 17 beta-Estradiol has been shown to inhibit Cl- secretion in rat distal colon through a nongenomic pathway. We examined whether 17 beta-estradiol inhibits Cl- secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17 beta-estradiol on cholera toxin and heat-stable enterotoxin induced Cl- secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral channel and apical Cl- channel activity, respectively. 17 beta-Estradiol dose-dependently inhibited secretory responses to both toxins with IC50 values of approximately 1 nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17 beta-Estradiol responses were insensitive to the pure antiestrogen ICI 182,720. 17 beta-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCS activation. In nystatin-permeabilized tissues, apical Cl- currents were unaffected by 17 beta-estradiol treatment while basolateral le current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17 beta-estradiol inhibits enterotoxin-induced Cl- secretion via a PKCS-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17 beta-estradiol inhibition of Cl- secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases. (C) 2011 Elsevier Inc. All rights reserved.