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Mechanosensitive gating of CFTR

Nature Cell Biology volume 12, pages 507–512 (2010)Cite this article

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A Corrigendum to this article was published on 01 August 2010

An Erratum to this article was published on 01 July 2010

This article has been updated

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion and intracellular ligand-gated channel associated with cystic fibrosis, a lethal genetic disorder common among Caucasians1. Here we show that CFTR is robustly activated by membrane stretch induced by negative pressures as small as 5 mmHg at the single-channel, cellular and tissue levels. Stretch increased the product of the number of channels present and probability of being open (NPo), and also increased the unitary conductance of CFTR in cell-attached membrane patches. CFTR stretch-mediated activation appears to be an intrinsic property independent of cytosolic factors and kinase signalling. CFTR stretch-mediated activation resulted in chloride transport in Calu-3 human airway epithelial cells and mouse intestinal tissues. Our study has revealed an unexpected function of CFTR in mechanosensing, in addition to its roles as a ligand-gated anion channel1 and a regulator of other membrane transporters2, demonstrating for the first time a mechanosensitive anion channel with a clearly defined molecular identity. Given that CFTR is often found in mechanically dynamic environments, its mechanosensitivity has important physiological implications in epithelial ion transport and cell volume regulation in vivo.

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Figure 1: Stretch increased CFTR NPo in cell-attached membrane patches of Calu-3 cells.
Figure 2: Membrane stretch increased CFTR single-channel current amplitude in cell-attached membrane patches of Calu-3 cells.
Figure 3: Stretch increased CFTR NPo in excised, inside-out membrane patches of Calu-3 cells in the absence of ATP.
Figure 4: Membrane stretch stimulated CFTR-mediated anion secretion in Calu-3 cells.
Figure 5: Membrane stretch activated CFTR-mediated anion secretion in mouse intestinal tissues.

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Change history

  • 09 July 2010

    In the version of this letter initially published online, Fig. 4e–j were incorrectly labelled. This error has been corrected in both the HTML and PDF versions of the letter.

  • 09 June 2010

    In the version of this letter initially published online, Fig. 1b and Fig 5e were incorrectly labelled. This error has been corrected in both the HTML and PDF versions of the letter.

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Acknowledgements

We thank R. Madhavan for stimulating discussion, J.M. Stutts for critical reading of the manuscript and Changyan Xie for assistance in manuscript preparation. This work was supported by the Hong Kong Research Grants Council grant GRF661009 (to P.H.).

Author information

Author notes

  1. Dong Wang

    Present address: Current address: Department of Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford CA 94305, USA.,

  2. Wei Kevin Zhang and Dong Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Nano Science and Technology Program, The Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China

    Wei Kevin Zhang, Michael M.T. Loy & Pingbo Huang

  2. Department of Biology, The Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China

    Wei Kevin Zhang, Dong Wang, Yuanyuan Duan & Pingbo Huang

  3. Department of Physics, The Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China

    Michael M.T. Loy

  4. Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China

    Hsiao Chang Chan

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Contributions

W.K.Z, D.W. and P.H. conceived the study and P.H. directed the study; W.K.Z performed and analysed most of the patch-clamp work with some help from D.W.; D.W. performed and analysed most of the Ussing chamber work with some help from W.K.Z and D.Y.; M.M.T.L designed the Ussing chamber adapted for pressure applications; H.C.C. provided Cftr knockout mice, critical comments and revision of the manuscript; P.H., W.K.Z. and D.W. drafted the manuscript; and P.H. revised the manuscript with contributions from all the authors.

Corresponding author

Correspondence to Pingbo Huang.

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The authors declare no competing financial interests.

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Zhang, W., Wang, D., Duan, Y. et al. Mechanosensitive gating of CFTR. Nat Cell Biol 12, 507–512 (2010). https://doi.org/10.1038/ncb2053

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