Role of Ca2+ -activated ion transport in the treatment of cystic fibrosis.

Cystic fibrosis (CF) is caused by defective cyclic AMP-dependent cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. Therefore, CF epithelial cells fail to transport, Cl(-) and water. Furthermore, the cessation of Cl(-) efflux across the apical membrane of CF pancreatic and biliary duct cells reduces HCO(3) (-) secretion as well. In CF epithelial cells activation of calcium-dependent Cl(-) channels might substitute for impaired CFTR function and restore Cl(-) and/or HCO(3) (-) secretion. ATP-mediated stimulation of P2Y and P2X purinergic receptors causes an increase in cytosolic Ca(2+) concentration ([Ca(2+)](i)). Effects of ATP are influenced by external zinc, pH and Na(+) concentrations. In low Na(+), alkaline environment, ATP and zinc induce a sustained and reproducible Ca(2+) signal because of P2X receptor mediated Ca(2+) influx from the extracellular space. Importantly, the increase in [Ca(2+)](i) stimulates anion secretion of nasal epithelia in CF mouse models suggesting that targeting P2X receptors might have beneficial effects in CF therapy.