Ivacaftor:CFTR G551D transports Cl- from cytosol to extracellular region

Stable Identifier
R-HSA-5678992
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Cystic fibrosis transmembrane conductance regulator (CFTR) is a low conductance chloride-selective channel that mediates the transport of chloride ions in human airway epithelial cells which plays a key role in maintaining homoeostasis of epithelial secretions in the lungs. Defects in CFTR can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver. Wide-ranging manifestations of the disease include chronic lung disease, exocrine pancreatic insufficiency, blockage of the terminal ileum, male infertility and salty sweat.

The class 3 mutations of CFTR such as G551D strongly decrease the time spent by CFTR in the open state (a gating defect). Results from 2-phase clinical trials using VX-770 (aka Ivacaftor), a CFTR potentiator, showed an increased CFTR channel open probability in G551D patients. Ivacaftor use showed improvements in CFTR and lung function of patients with at least one G551D allele (Accurso et al. 2010, Ramsey et al. 2011, Kapoor et al. 2014). In 2012, the FDA approved Ivacaftor (under the trade name Kalydeco) for use in cystic fibrosis patients with the G551D mutation (Ledford 2012).

Literature References
PubMed ID Title Journal Year
22318583 Drug bests cystic-fibrosis mutation

Ledford, H

Nature 2012
21083385 Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation

Accurso, FJ, Rowe, SM, Clancy, JP, Boyle, MP, Dunitz, JM, Durie, PR, Sagel, SD, Hornick, DB, Konstan, MW, Donaldson, SH, Moss, RB, Pilewski, JM, Rubenstein, RC, Uluer, AZ, Aitken, ML, Freedman, SD, Rose, LM, Mayer-Hamblett, N, Dong, Q, Zha, J, Stone, AJ, Olson, ER, Ordoñez, CL, Campbell, PW, Ashlock, MA, Ramsey, BW

N. Engl. J. Med. 2010
25584290 Ivacaftor: a novel mutation modulating drug

Kapoor, H, Koolwal, A, Singh, A

J Clin Diagn Res 2014
22047557 A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

Ramsey, BW, Davies, J, McElvaney, NG, Tullis, E, Bell, SC, Dřevínek, P, Griese, M, McKone, EF, Wainwright, CE, Konstan, MW, Moss, R, Ratjen, F, Sermet-Gaudelus, I, Rowe, SM, Dong, Q, Rodriguez, S, Yen, K, Ordoñez, C, Elborn, JS

N. Engl. J. Med. 2011
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
chloride transmembrane transporter activity of Ivacaftor:CFTR G551D [plasma membrane]
Physical Entity
Activity
Normal reaction
Disease
Name Identifier Synonyms
cystic fibrosis 1485 mucoviscidosis, CF
Authored
Reviewed
Created
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