Ko Shigeru B H, Zeng Weizhong, Dorwart Michael R, Luo Xiang, Kim Kil Hwan, Millen Linda, Goto Hidemi, Naruse Satoru, Soyombo Abigail, Thomas Philip J, Muallem Shmuel
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA.
Nat Cell Biol. 2004 Apr;6(4):343-50. doi: 10.1038/ncb1115. Epub 2004 Mar 28.
Chloride absorption and bicarbonate secretion are vital functions of epithelia, as highlighted by cystic fibrosis and diseases associated with mutations in members of the SLC26 chloride-bicarbonate exchangers. Many SLC26 transporters (SLC26T) are expressed in the luminal membrane together with CFTR, which activates electrogenic chloride-bicarbonate exchange by SLC26T. However, the ability of SLC26T to regulate CFTR and the molecular mechanism of their interaction are not known. We report here a reciprocal regulatory interaction between the SLC26T DRA, SLC26A6 and CFTR. DRA markedly activates CFTR by increasing its overall open probablity (NP(o)) sixfold. Activation of CFTR by DRA was facilitated by their PDZ ligands and binding of the SLC26T STAS domain to the CFTR R domain. Binding of the STAS and R domains is regulated by PKA-mediated phosphorylation of the R domain. Notably, CFTR and SLC26T co-localize in the luminal membrane and recombinant STAS domain activates CFTR in native duct cells. These findings provide a new understanding of epithelial chloride and bicarbonate transport and may have important implications for both cystic fibrosis and diseases associated with SLC26T.
氯离子吸收和碳酸氢根分泌是上皮细胞的重要功能，囊性纤维化以及与SLC26氯离子-碳酸氢根交换体成员突变相关的疾病就突出了这一点。许多SLC26转运蛋白（SLC26T）与CFTR一起表达于管腔膜中，CFTR可激活SLC26T介导的电中性氯离子-碳酸氢根交换。然而，SLC26T调节CFTR的能力及其相互作用的分子机制尚不清楚。我们在此报告了SLC26T DRA、SLC26A6与CFTR之间的相互调节作用。DRA通过将CFTR的整体开放概率（NP(o)）提高六倍，从而显著激活CFTR。DRA对CFTR的激活作用因它们的PDZ配体以及SLC26T STAS结构域与CFTR R结构域的结合而得到促进。STAS结构域与R结构域的结合受PKA介导的R结构域磷酸化调控。值得注意的是，CFTR与SLC26T共定位于管腔膜中，并且重组STAS结构域可在天然导管细胞中激活CFTR。这些发现为上皮细胞氯离子和碳酸氢根转运提供了新的认识，可能对囊性纤维化以及与SLC26T相关的疾病都具有重要意义。
