Cystic fibrosis transmembrane conductance regulator-associated ATP release is controlled by a chloride sensor.
Cystic fibrosis transmembrane conductance regulator-associated ATP release is controlled by a chloride sensor.
复制标题
囊性纤维化跨膜电导调节剂相关的ATP释放由氯化物传感器控制。
DOI：
10.1083/jcb.143.3.645
复制
发表时间：
1998-11-02
影响因子：
7.8
通讯作者：
Engelhardt, J F
中科院分区：
文献类型：
--
作者：
Jiang, Q;Mak, D;Devidas, S;Schwiebert, E M;Bragin, A;Zhang, Y;Skach, W R;Guggino, W B;Foskett, J K;Engelhardt, J F
囊性纤维化跨膜传导调节因子（CFTR）是一种在囊性纤维化中有缺陷的氯离子通道，并且也与细胞中的ATP渗透性密切相关。使用非洲爪蟾卵母细胞cRNA表达系统，我们已经评估了控制CFTR调节ATP释放的分子机制。CFTR调节的ATP释放依赖于cAMP激活和细胞外氯离子浓度的梯度变化。ATP释放的激活发生在一个狭窄的外部Cl-浓度范围内，这与气道表面液体中报告的相似。CFTR的突变表明，Cl−传导和ATP释放调节特性可以分离到CFTR蛋白的不同区域。尽管不需要Cl−通过CFTR传导来调节ATP释放，但通道孔残基R347和R334的改变导致不同卤化物激活ATP流出的相对能力发生变化（wtCFTR，Cl >> Br; R347 P，Cl >> Br; R347 E，Br >> Cl; R334 W，Cl = Br）。我们假设残基R347和R334可能在CFTR通道孔内提供了一个Cl−结合位点，该位点对于响应细胞外Cl−增加而激活ATP流出是必需的。总之，这些发现表明一种新的氯离子传感器机制，CFTR能够通过调节未识别的ATP外排途径的活性来响应细胞外氯离子浓度的变化。该通路可能通过嘌呤能调节上皮细胞在维持气道液体和电解质平衡中发挥重要作用。对这些分子机制的深入了解增强了我们对囊性纤维化肺发病机制的理解。
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is defective in cystic fibrosis, and has also been closely associated with ATP permeability in cells. Using a Xenopus oocyte cRNA expression system, we have evaluated the molecular mechanisms that control CFTR-modulated ATP release. CFTR-modulated ATP release was dependent on both cAMP activation and a gradient change in the extracellular chloride concentration. Activation of ATP release occurred within a narrow concentration range of external Cl− that was similar to that reported in airway surface fluid. Mutagenesis of CFTR demonstrated that Cl− conductance and ATP release regulatory properties could be dissociated to different regions of the CFTR protein. Despite the lack of a need for Cl− conductance through CFTR to modulate ATP release, alterations in channel pore residues R347 and R334 caused changes in the relative ability of different halides to activate ATP efflux (wtCFTR, Cl >> Br; R347P, Cl >> Br; R347E, Br >> Cl; R334W, Cl = Br). We hypothesize that residues R347 and R334 may contribute a Cl− binding site within the CFTR channel pore that is necessary for activation of ATP efflux in response to increases of extracellular Cl−. In summary, these findings suggest a novel chloride sensor mechanism by which CFTR is capable of responding to changes in the extracellular chloride concentration by modulating the activity of an unidentified ATP efflux pathway. This pathway may play an important role in maintaining fluid and electrolyte balance in the airway through purinergic regulation of epithelial cells. Insight into these molecular mechanisms enhances our understanding of pathogenesis in the cystic fibrosis lung.