Letter abstract
Nature Cell Biology 6, 343 - 350 (2004)
Published online: 28 March 2004 | doi:10.1038/ncb1115
Gating of CFTR by the STAS domain of SLC26 transporters
Shigeru B.H. Ko1,3, Weizhong Zeng1, Michael R. Dorwart1,2, Xiang Luo1, Kil Hwan Kim1, Linda Millen1, Hidemi Goto3, Satoru Naruse3, Abigail Soyombo1, Philip J. Thomas1 & Shmuel Muallem1
Chloride absorption and bicarbonate secretion are vital functions of epithelia1, 2, 3, 4, 5, 6, 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 CFTR7, which activates electrogenic chloride-bicarbonate exchange by SLC26T8. 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 (NPo) 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.
- Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA.
- Graduate program in Molecular Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA.
- Division of Gastroenterology, Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Correspondence to: Shmuel Muallem1 e-mail: shmuel.muallem@utsouthwestern.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Bicarbonate secretion: it takes two to tangoNature Cell Biology News and Views (01 Apr 2004)
Rules of conduct for the cystic fibrosis anion channelNature Medicine News and Views (01 Jul 2003)
See all 3 matches for News And ViewsRESEARCH
A molecular mechanism for aberrantCFTR-dependent HCO 3 − transport in cystic fibrosisThe EMBO Journal Article (01 Nov 2002)
Metabolon disruption: a mechanism that regulates bicarbonate transportThe EMBO Journal Article (20 Jul 2005)
See all 14 matches for Research
