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Description

The cystic fibrosis (CF) gene encodes a cAMP-regulated chloride channel, the CF transmembrane conductance regulator (CFTR). A glycine-to-aspartic acid missense mutation at codon 551 (G551D) is a common mutation associated with a severe CF phenotype. Ivacaftor is an orally bioavailable CFTR potentiator that improves chloride transport. It increases the forskolin-induced CFTR-mediated epithelial current in cells expressing the G551D mutation by ~4-fold (EC50 = 100 nM) but has no effect on current in the absence of forskolin. Ivacaftor increases chloride secretion in cultured human CF bronchial epithelial cells carrying the G551D mutation on one allele and the common delta F508 processing mutation on the other allele. It binds CFTR directly and causes CFTR channel opening by an ATP-independent mechanism. It effectively improves sweat chloride in vivo while improving lung function when at least one G551D CFTR mutation is present.