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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel
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Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel

机译：维生素C控制囊性纤维化跨膜电导调节剂氯通道

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摘要

Vitamin C (L-ascorbate) is present in the respiratory lining fluid of human lungs, and local deficits occur during oxidative stress. Here we report a unique function of vitamin C on the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), a cAMP-dependent Cl channel that regulates epithelial surface fluid secretion. Vitamin C (100 muM) induced the openings of CFTR Cl channels by increasing its average open probability from 0 to 0.21 +/- 0.08, without a detectable increase in intracellular cAMP levels. Exposure of the apical airway surface to vitamin C stimulated the transepithelial Cl secretion to 68% of forskolin-stimulated currents. The average half-maximal stimulatory constant was 36.5 +/- 2.9 muM, which corresponds to physiological concentrations. When vitamin C was instilled into the nasal epithelium of human subjects, it effectively activated Cl transport in vivo. In CF epithelia, previous treatment of the underlying trafficking defect with trimethylamine oxide or expression of WT CFTR restored the activation of Cl transport by vitamin C. Sodium dependency and phloretin sensitivity, as well as the expression of transcripts for sodium-dependent vitamin C transporter (SVCT)-1 and SVCT2, support a model in which an apical vitamin C transporter is central for relaying the effect of vitamin C to CFTR. We conclude that cellular vitamin C is a biological regulator of CFTR-mediated Cl secretion in epithelia. The pool of vitamin C in the respiratory tract represents a potential nutraceutical and pharmaceutical target for the complementary treatment of sticky airway secretions by enhancing epithelial fluid secretion. [References: 48]
机译：维生素C（L-抗坏血酸）存在于人肺的呼吸内膜液中，在氧化应激期间会出现局部缺陷。在这里，我们报告了维生素C在囊性纤维化（CF）跨膜电导调节器（CFTR）上的独特功能，这是一种cAMP依赖性Cl通道，可调节上皮表面液的分泌。维生素C（100μM）通过将CFTR Cl通道的平均打开概率从0增加到0.21 +/- 0.08来诱导CFTR Cl通道的打开，而细胞内cAMP水平却没有可检测到的增加。顶端气道表面暴露于维生素C可以刺激上皮Cl分泌达到Forskolin刺激电流的68％。平均半最大刺激常数为36.5 +/- 2.9μM，与生理浓度相对应。将维生素C滴入人类受试者的鼻上皮后，可有效激活体内的Cl转运。在CF上皮细胞中，先前用三甲胺氧化物或WT CFTR的表达治疗潜在的运输缺陷，恢复了维生素C对Cl转运的激活。钠依赖性和促性腺激素敏感性以及钠依赖性维生素C转运蛋白的转录本表达（ SVCT）-1和SVCT2支持一种模型，其中顶端的维生素C转运蛋白是将维生素C的作用传递给CFTR的中心。我们得出结论，细胞维生素C是上皮细胞CFTR介导的Cl分泌的生物调节剂。呼吸道中的维生素C库代表通过增强上皮液分泌来补充治疗气道粘稠分泌物的潜在营养保健和药物靶标。 [参考：48]

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