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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TWO CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS HAVE DIFFERENT EFFECTS ON BOTH PULMONARY PHENOTYPE AND REGULATION OF OUTWARDLY RECTIFIED CHLORIDE CURRENTS
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TWO CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS HAVE DIFFERENT EFFECTS ON BOTH PULMONARY PHENOTYPE AND REGULATION OF OUTWARDLY RECTIFIED CHLORIDE CURRENTS

机译：两种囊性纤维化跨膜电导调节剂突变对肺表型和向外整流的氯离子流的调节都有不同的作用

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Cystic fibrosis (CF), a disorder of electrolyte transport manifest in the lungs, pancreas, sweat duct, and vas deferens, is caused by mutations in the CF transmembrane conductance regulator (CFTR). The CFTR protein has been shown to function as a cAMP-activated chloride channel and also regulates a separate protein, the outwardly rectifying chloride channel (ORCC). To determine the consequence of disease-producing mutations upon these functions, mutant CFTR was transiently expressed in Xenopus oocytes and in human airway epithelial cells lacking functional CFTR, Both G551D, a mutation that causes severe lung disease, and A455E, a mutation associated with mild lung disease, altered but did not abolish CFTR's function as a chloride channel in Xenopus oocytes. Airway epithelial cells transfected with CFTR bearing either A455E or G551D had levels of chloride conductance significantly greater than those of mock-transfected and lower than those of wild-type CFTR-transfected cells, as measured by chloride efflux. A combination of channel blockers and analysis of current-voltage relationships were used to dissect the contribution of CFTR and the ORCC to whole cell currents of transfected cells, While CFTR bearing either mutation could function as a chloride channel, only CFTR bearing A455E retained the function of regulating the ORCC, These results indicate that CF mutations can affect CFTR functions differently and suggest that severity of pulmonary disease may be more closely associated with the regulatory rather than chloride channel function of CFTR. [References: 31]
机译：囊性纤维化（CF）是一种在肺，胰腺，汗管和输精管中出现的电解质运输紊乱，是由CF跨膜电导调节器（CFTR）的突变引起的。 CFTR蛋白已显示出可作为cAMP激活的氯离子通道的功能，并且还调节单独的蛋白质，即向外整流的氯离子通道（ORCC）。为了确定在这些功能上引起疾病的突变的后果，突变的CFTR在非洲爪蟾卵母细胞和缺乏功能CFTR的人气道上皮细胞中瞬时表达，G551D（引起严重的肺部疾病的突变）和A455E（与轻度相关的突变）肺部疾病，已改变但并未取消CFTR在非洲爪蟾卵母细胞中作为氯通道的功能。通过氯离子外流测量，用CFTR转染了A455E或G551D的气道上皮细胞的氯传导水平显着高于模拟转染的细胞，而低于野生型CFTR转染的细胞。结合通道阻滞剂和电流-电压关系分析来剖析CFTR和ORCC对转染细胞全细胞电流的贡献。尽管带有任一突变的CFTR都可以充当氯离子通道，但是只有带有A455E的CFTR保留了该功能这些结果表明，CF突变可以不同地影响CFTR的功能，提示肺部疾病的严重程度可能与CFTR的调节通道而不是氯通道功能密切相关。 [参考：31]

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