Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel
Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel
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DOI：
10.1073/pnas.0308393100
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Illek, B
中科院分区：
文献类型：
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作者：
Fischer, H;Schwarzer, C;Illek, B
维生素C(L-抗坏血酸)存在于人肺的呼吸衬里液体中，在氧化应激过程中会出现局部缺陷。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(CFTR)上的独特功能，CFTR是一种依赖cAMP的氯通道，调节上皮细胞表面液体的分泌。维生素C(100um)可使CFTRCl通道的平均开放概率从0增加到0.21+/-0.08，而细胞内cAMP水平未见明显升高。顶端呼吸道表面暴露于维生素C可刺激68%的Forsklin刺激电流的跨上皮氯离子分泌。平均半最大刺激常数为36.5+/-2.9um，与生理浓度相对应。将维生素C注入人体鼻腔上皮，可有效地激活体内氯离子转运。在CF上皮细胞中，用三甲胺氧化物处理潜在的转运缺陷或表达WT CFTR可以恢复维生素C对氯离子转运的激活，钠依赖和根素敏感性，以及钠依赖的维生素C转运体(SVCT)-1和SVCT2的转录本的表达，支持一个模型，在该模型中，顶端维生素C转运体是将维生素C的作用传递到CFTR的中心。我们的结论是，细胞内的维生素C是CFTR介导的上皮细胞氯分泌的生物调节因子。呼吸道中的维生素C池是一种潜在的营养和药物靶点，可通过促进上皮液分泌来补充治疗粘性呼吸道分泌物。
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.