Mechanosensitive gating of CFTR.
Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion and intracellular ligand-gated channel associated with cystic fibrosis, a lethal genetic disorder common among Caucasians. 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 channel and a regulator of other membrane transporters, 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.
Zhang
Wei Kevin
WK
Nano Science and Technology Program, The Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China.
Wang
Dong
D
Duan
Yuanyuan
Y
Loy
Michael M T
MM
Chan
Hsiao Chang
HC
Huang
Pingbo
P
D000818:Animals; D001692:Biological Transport; D001696:Biomechanical Phenomena; D048429:Cell Size; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism* / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D011312:Pressure; D013314:Stress, Mechanical
D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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