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Updated: Mar 28, 2026
10:05
In Vitro Analysis of PDZ-dependent CFTR Macromolecular Signaling Complexes
Published on: August 13, 2012
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Mechanosensitivity of wild-type and G551D cystic fibrosis transmembrane conductance regulator (CFTR) controls
Changyan Xie1, Xu Cao1, Xibing Chen1
1*Division of Life Science, Division of Biomedical Engineering, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
Summary
Mechanical forces directly activate both normal and G551D cystic fibrosis transmembrane conductance regulator (CFTR) channels, revealing a new mechanism for epithelial volume regulation and explaining milder disease phenotypes.
Area of Science:
- Cell Biology
- Physiology
- Genetics
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) mutations cause cystic fibrosis, a lethal genetic disease.
- The G551D CFTR mutation impairs ATP hydrolysis, hindering cAMP stimulation.
- CFTR's role in regulatory volume decrease (RVD) is known but mechanistically unclear.
Purpose of the Study:
- To investigate the direct mechanical regulation of CFTR channel activity.
- To elucidate the role of CFTR mechanosensitivity in epithelial RVD.
- To understand the impact of the G551D mutation on CFTR-mediated RVD.
Main Methods:
- Single-channel recordings in cell-attached patches.
- Measurement of short-circuit current (Isc) in Calu-3 cells and mouse duodena.
- Genetic manipulation (suppression, ablation) and pharmacological inhibition of CFTR.
Main Results:
- Hypotonicity and mechanical stretch directly activated both wild-type (WT) and G551D CFTR channels, independent of Ca(2+) and cAMP/PKA.
- CFTR gene ablation, but not G551D mutation, suppressed hypotonicity- and stretch-induced Isc.
- CFTR channel activity, including that of G551D CFTR, is essential for epithelial RVD, as shown by blocker experiments.
Conclusions:
- CFTR channel activity is directly mechanosensitive, playing a crucial role in epithelial RVD.
- The mechanosensitivity of G551D CFTR may contribute to the milder clinical presentation of this specific mutation.
- This study uncovers a novel mechanism for CFTR function in epithelial homeostasis.
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