Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel and its genetic mutations cause cystic fibrosis, a lethal genetic disorder common among Caucasians. CFTR channel gating is subject to ATP hydrolysis and phosphorylation and therefore CFTR is traditionally viewed as an intracellular ligand-gated ion channel. Here we show that the 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 channel number and open probability (NP_o) and the unitary conductance of CFTR in cell-attached membrane patches. CFTR stretch-activation appears to be an intrinsic property independent of cytosolic factors and kinase signaling, because stretch could activate...[ Read more ]

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel and its genetic mutations cause cystic fibrosis, a lethal genetic disorder common among Caucasians. CFTR channel gating is subject to ATP hydrolysis and phosphorylation and therefore CFTR is traditionally viewed as an intracellular ligand-gated ion channel. Here we show that the 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 channel number and open probability (NP_o) and the unitary conductance of CFTR in cell-attached membrane patches. CFTR stretch-activation appears to be an intrinsic property independent of cytosolic factors and kinase signaling, because stretch could activate CFTR in excised, inside-out membrane patches without ATP. Significantly, CFTR stretch-activation resulted in chloride transport in Calu-3 human airway epithelia cells and mouse intestinal tissues. Our study has revealed an unexpected function of CFTR in mechano-sensing, in addition to its roles as a ligand-gated anion channel and a regulator of other membrane transporters, demonstrating for the first time a mechano-sensitive anion channel with a clearly defined molecular identity. Given that CFTR is often found in mechanically dynamic environments, its mechano-sensitivity has important physiological implications in epithelial ion transport and cell volume regulation in vivo.