期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：16
页码：9620-9625
DOI：10.1073/pnas.1633250100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Dynamic regulation of ion channels is critical for maintaining fluid balance in epithelial tissues. Cystic fibrosis, a genetic disease characterized by impaired fluid transport in epithelial tissues, is caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel activity. Recent studies have shown that binding of PSD-95/Dlg/ZO-1 (PDZ) domain proteins to CFTR is important for retaining it at the apical membrane and for regulating its channel activity. Here, we describe a phosphorylation mechanism that regulates CFTR channel activity, which is mediated by PDZ domains. The Na+/H+ exchanger regulatory factor (NHERF) binds to CFTR and increases its open probability (Po). Protein kinase C disrupts the stimulatory effect of NHERF on CFTR channel Po. Phosphorylation by PKC of Ser-162 in the PDZ2 domain of NHERF is critical for this functional effect. Furthermore, a mutation in PDZ2 that mimics phosphorylation decreases CFTR binding and disrupts the ability of NHERF PDZ1-2 to stimulate CFTR channel Po. Our results identify a role for PKC and suggest that phosphorylation of NHERF PDZ2 domain may be an important mechanism for regulating CFTR channel activity.
