Cystic fibrosis transmembrane conductance regulator (CFTR) is anion channel responsible for anion transport in various epithelial cells and therefore plays a critically important role in the normal function of the lungs, pancreas, bile ducts, and the intestinal and reproductive tracts.Genetic mutations of CFTR cause cystic fibrosis disease.On the other hand, over-activation of CFTR by cholera toxin is a common cause of secretory diarrhea in developing countries.Therefore, CFTR is a very important therapeutic target.CFTR is traditionally viewed as an intracellular ligand-gated ion channel.Recently, we have found that the CFTR channel was 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 activity (NPo) and unitary conductance of CFTR.Stretch activation of CFTR is an intrinsic property that is independent of Ca2+ and cAMP signaling.CFTR stretch activation resulted in chloride transport in epithelial cells.Our study has revealed an unexpected function of CFTR, in addition to its roles as a ligand-gated anion channel and as a regulator of other membrane transporters, and is the first to report a mechanosensitive anion channel with a clearly defined molecular identity.In addition, we have found that CFTR single channel is activated by hypotonic challenge and CFTR channel activities is involved in swelling-induced anion secretion and regulatory volume decrease (RVD).Our data suggest that CFTR is a stretch-and volume-sensitive channel and its mechanosensitivity has important physiological implications.The work was supported by RGC grant GRF661009.