Vitamin C Controls the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 10; pp. 3691 - 3696
• Main Authors: Fischer, Horst, Schwarzer, Christian, Illek, Beate, Ames, Bruce N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.03.2004; National Acad Sciences
• Subjects: Agonists; Animals; Ascorbic Acid - pharmacology; Base Sequence; Biological Sciences; Cell Line; Cell lines; Cell membranes; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - drug effects; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; DNA, Complementary - genetics; Epithelial cells; Fluids; Functional foods & nutraceuticals; Gene Expression; Genetic mutation; Humans; In Vitro Techniques; Ion Transport - drug effects; Ions; Lungs; Membranes; Mice; Mice, Inbred CFTR; Molecular biology; Molecular Sequence Data; Mutation; Organic Anion Transporters, Sodium-Dependent - genetics; Organic Anion Transporters, Sodium-Dependent - metabolism; Oxidative stress; Respiratory system; Respiratory System - cytology; Respiratory System - drug effects; Respiratory System - metabolism; Respiratory tract; Salts; Secretion; Sodium; Sodium-Coupled Vitamin C Transporters; Symporters - genetics; Symporters - metabolism; Vitamin C
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0308393100

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), cAMP-dependent Cl channel that regulates epithelial surface fluid secretion. Vitamin C (100 μM) 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 CI secretion to 68% of forskolin-stimulated currents. The average half-maximal stimulatory constant was 36.5 ± 2.9 μM, 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.