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首页> 外文期刊>Molecular membrane biology >Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by niflumic acid.
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Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by niflumic acid.

机译：尼氟胺酸直接阻断囊性纤维化跨膜电导调节器Cl（-）通道。

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摘要

Niflumic acid is widely used to inhibit Ca(2+) -activated Cl(-) channels. However, the chemical structure of niflumic acid resembles that of diphenylamine-2-carboxylate, a drug that inhibits the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. To investigate how niflumic acid inhibits CFTR Cl(-) channel, we studied recombinant wild-type human CFTR in excised inside-out membrane patches. When added to the intracellular solution, niflumic acid caused a concentration- and voltage-dependent decrease of CFTR Cl(-) current with half-maximal inhibitory concentration (K(i)) of 253 microM and Hill co-efficient of approximately 1, at -50 mV. Niflumic acid inhibition of single CFTR Cl(-) channels was characterized by a very fast, flickery block that decreased dramatically current amplitude without altering open-probability. Consistent with these data, spectral analysis of CFTR Cl(-) currents suggested that channel block by niflumic acid was described by the closed <--> open <--> blocked kinetic scheme with blocker on rate (k(on)) = 13.9 x 10(6) M(-1)s(-1), off rate (k(off))=3348 s(-1) and dissociation constant (K(d)) = 241 microM, at -50 mV. Based on these data, we tested the effects of niflumic acid on transepithelial Cl(-) secretion and cyst growth using type I MDCK epithelial cells. Niflumic acid (200 microM) inhibited cAMP-stimulated, bumetanide-sensitive short-circuit current by 55%. Moreover, the drug potently retarded cyst growth. We conclude that niflumic acid is an open-channel blocker of CFTR that inhibits Cl(-) permeation by plugging the channel pore. It or related agents might be of value in the development of new therapies for autosomal dominant polycystic kidney disease.
机译：尼氟酸广泛用于抑制Ca（2+）激活的Cl（-）通道。但是，尼氟酸的化学结构类似于二苯胺-2-羧酸盐（一种抑制囊性纤维化跨膜电导调节剂（CFTR）Cl（-）通道的药物）的化学结构。为了研究尼氟酸如何抑制CFTR Cl（-）通道，我们研究了在切除的内外膜片中的重组野生型人CFTR。当添加到细胞内溶液中时，尼氟酸会导致CFTR Cl（-）电流的浓度和电压依赖性下降，最大抑制浓度（K（i））的一半为253 microM，希尔系数约为1， -50毫伏。单个CFTR Cl（-）通道的尼氟酸抑制作用的特征是非常快速的闪烁块，该闪烁块可显着降低电流幅度而不会改变打开概率。与这些数据一致，CFTR Cl（-）电流的频谱分析表明，尼古拉丁酸对通道的阻断作用是通过封闭的打开状态（k（on））= 13.9的封闭的打开的封闭的动力学方案描述的。 x 50（6）M（-1）s（-1），关闭速率（k（off））= 3348 s（-1）和解离常数（K（d））= 241 microM，在-50 mV下。根据这些数据，我们使用I型MDCK上皮细胞测试了烟酸对跨上皮Cl（-）分泌和囊肿生长的影响。尼氟酸（200 microM）可抑制cAMP刺激的布美他尼敏感短路电流55％。而且，该药物有效地延迟了囊肿的生长。我们得出的结论是，尼氟酸是CFTR的开放通道阻滞剂，可通过堵塞通道孔来抑制Cl（-）渗透。它或相关药物在常染色体显性多囊肾疾病的新疗法的开发中可能有价值。

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