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Gating of CFTR by the STAS domain of SLC26 transporters

Nature Cell Biology volume 6, pages 343–350 (2004)Cite this article

Abstract

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.

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Figure 1: Role of the PDZ ligands in the interaction between the STAS and R domains.
Figure 2: Activation of CFTR by DRA and SLC26A6.
Figure 3: STAS domain activation of CFTR requires intact STAS and R domains.
Figure 4: Activity of STAS in vivo.
Figure 5: A model for ductal chloride absorption and bicarbonate secretion.

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Acknowledgements

This work was supported by grants DE12309, DK38938, cystic fibrosis Foundation grant MUALLE01G0 (to S.M.), DK49835 (to P.T.), traning grant GM-08203 (M.R.D.), Pancreas Research Foundation of Japan (to S.K.) and the Ministry of Education, Science, Technology, Sports and Culture, Japan, and the Uehara Memorial Foundation (to S.N.). S.B.H.K. was supported by the Japan Health Sciences Foundation.

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Authors and Affiliations

  1. Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, 75390-9040, TX, USA

    Shigeru B.H. Ko, Weizhong Zeng, Michael R. Dorwart, Xiang Luo, Kil Hwan Kim, Linda Millen, Abigail Soyombo, Philip J. Thomas & Shmuel Muallem

  2. Graduate program in Molecular Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, 75390-9040, TX, USA

    Michael R. Dorwart

  3. Division of Gastroenterology, Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan

    Shigeru B.H. Ko, Hidemi Goto & Satoru Naruse

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  1. Shigeru B.H. Ko
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Correspondence to Shmuel Muallem.

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Ko, S., Zeng, W., Dorwart, M. et al. Gating of CFTR by the STAS domain of SLC26 transporters. Nat Cell Biol 6, 343–350 (2004). https://doi.org/10.1038/ncb1115

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