Ivacaftor potentiation of multiple CFTR channels with gating mutations.

The use of ivacaftor in CFTR mutations resulting in residual functioning protein

INTRODUCTION Ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) potentiator is currently approved for use in individuals with class III gating mutations and the R117H mutation, a non-gating mutation with residual functioning CFTR. Nevertheless, ivacaftor may also be effective in individuals who have CF mutations giving rise to a residual functioning protein. However, aside from case re...

Ivacaftor in a young boy with the rare gating mutation S549R--use of lung clearance index to track progress: a case report.

BACKGROUND Ivacaftor acts as a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and increases the transepithelial chloride transport of CFTR in 9 of 10 known gating mutations causing cystic fibrosis. S549R is a rare gating mutation considered to be less sensitive to potentiators than all other gating mutations. CASE PRESENTATION We report our first experience with...

Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization

In CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) opens the pore, and dimer disruption following ATP hydrolysis closes it. Spontaneous openings without ATP are rare in wild-type CFTR, but in certain CF mutants constitute the only gating mechanism, stimulated by ivacaftor, a clinically appro...

Title: Synergistic Potentiation of CFTR gating by two chemically distinct potentiators, Ivacaftor (VX-770) and NPPB

Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation*

Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. ...