Lubiprostone activates CFTR, but not ClC-2, via the prostaglandin receptor (EP(4)).
Lubiprostone activates CFTR, but not ClC-2, via the prostaglandin receptor (EP(4)).
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DOI：
10.1016/j.bbrc.2012.08.097
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发表时间：
2012-09-28
影响因子：
3.1
通讯作者：
MacDonald, Kelvin D.
中科院分区：
文献类型：
--
作者：
Norimatsu, Yohei;Moran, Aurelia R.;MacDonald, Kelvin D.
本研究的目的是确定鲁比前列酮激活上皮细胞氯离子转运的机制。鲁比前列酮是一种被批准用于治疗便秘的双环脂肪酸。然而，鲁比前列酮如何增加上皮细胞氯离子转运尚不确定。已有研究描述了对ClC - 2和CFTR氯离子通道的直接刺激以及通过EP4受体对这些通道的刺激。为了更好地明确这一机制，采用双电极电压钳技术检测表达ClC - 2的非洲爪蟾卵母细胞（有或无EP4受体或β肾上腺素能受体（βAR）共表达）对鲁比前列酮引起的电导变化。还对共表达CFTR以及βAR或EP4受体的卵母细胞进行了研究。在共表达ClC - 2和βAR的卵母细胞中，超极化和酸性pH（pH = 6）可刺激电导，但对β肾上腺素能激动剂异丙肾上腺素无反应。仅表达ClC - 2或共表达ClC - 2和EP4的卵母细胞对灌流液中0.1、1或10 µM鲁比前列酮的存在无反应。共表达CFTR和βAR的卵母细胞对超极化、酸性pH或1 µM鲁比前列酮无反应。然而，异丙肾上腺素可使电导升高，CFTRinh172可使其降低。CFTR和EP4共表达导致鲁比前列酮刺激的电导，该电导对CFTRinh172也敏感。鲁比前列酮介导的CFTR激活的EC50约为10 nM。这些结果表明鲁比前列酮对卵母细胞中表达的ClC - 2或CFTR通道无直接作用。然而，结果证实CFTR可通过卵母细胞中的EP4受体被鲁比前列酮激活。
The goal of this study was to determine the mechanism of lubiprostone activation of epithelial chloride transport. Lubiprostone is a bicyclic fatty acid approved for the treatment of constipation. There is uncertainty, however, as to how lubiprostone increases epithelial chloride transport. Direct stimulation of ClC-2 and CFTR chloride channels as well as stimulation of these channels via the EP4 receptor has been described. To better define this mechanism, two-electrode voltage clamp was used to assay Xenopus oocytes expressing ClC-2, with or without co-expression of the EP4 receptor or β adrenergic receptor (βAR), for changes in conductance elicited by lubiprostone. Oocytes co-expressing CFTR and either βAR or the EP4 receptor were also studied. In oocytes co-expressing ClC-2 and βAR conductance was stimulated by hyperpolarization and acidic pH (pH=6), but there was no response to the β adrenergic agonist, isoproterenol. Oocytes expressing ClC-2 only or co-expressing ClC-2 and EP4 did not respond to the presence of 0.1, 1, or 10 µM lubiprostone in the superperfusate. Oocytes co-expressing CFTR and βAR did not respond to hyperpolarization, acidic pH, or 1µM lubiprostone. However, conductance was elevated by isoproterenol and inhibited by CFTRinh172. Co-expression of CFTR and EP4 resulted in lubiprostone-stimulated conductance, which was also sensitive to CFTRinh172. The EC50 for lubiprostone mediated CFTR activation was ~ 10 nM. These results demonstrate no direct action of lubiprostone on either ClC-2 or CFTR channels expressed in oocytes. However, the results confirm that CFTR can be activated by lubiprostone via the EP4 receptor in oocytes.
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影响因子：
11.4
作者：
Jordt, SE;Jentsch, TJ
通讯作者：
Jentsch, TJ
影响因子：
2.9
作者：
O'Brien, Catherine E.;Anderson, Paula J.;Stowe, Cindy D.
通讯作者：
Stowe, Cindy D.
影响因子：
3.5
作者：
FURUKAWA, T;HORIKAWA, S;HIRAOKA, M
通讯作者：
HIRAOKA, M
影响因子：
2.9
作者：
O'Brien, Catherine E.;Anderson, Paula J.;Stowe, Cindy D.
通讯作者：
Stowe, Cindy D.
囊性纤维化跨膜电导调节器CL-通道的电压依赖性门控。
影响因子：
3.8
作者：
Cai, Zhiwei;Scott-Ward, Toby S;Sheppard, David N
通讯作者：
Sheppard, David N