A src-like kinase activates outwardly rectifying chloride channels in CFTR-defective lymphocytes

Defective activation of chloride channels is a hallmark of cystic fibrosis (CF). Recently we have described activation of a volume-sensitive, outwardly rectifying chloride conductance (IOR) through the src-like tyrosine kinase p56lck. Here we show that p56lck activates IOR independently of CFTR. In lymphocytes from healthy donors, chloride channels could be opened by either intracellular cAMP, p56lck or osmotic swelling. In CF lymphocytes, p56lck and cell swelling but not cAMP could activate chloride channels. Regulation of IOR by p56lck thus represents an alternative pathway of stimulating membrane chloride conductance that is left intact in cystic fibrosis.—Lepple-Wienhues, A., Wieland, U., Laun, T., Heil, L., Stern, M., Lang, F. A src-like kinase activates outwardly rectifying chloride channels in CFTR-defective lymphocytes.