ABCMdb

PMID: 24796242

Kopeikin Z, Yuksek Z, Yang HY, Bompadre SG
Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels.
J Cyst Fibros. 2014 Sep;13(5):508-14. doi: 10.1016/j.jcf.2014.04.003. Epub 2014 May 3., [PubMed]

Sentences

No. Mutations Sentence Comment

26 ABCC7 p.Gly551Asp VX-770 (Ivacaftor) is the first CFTR potentiator approved by the Food and Drug Administration (USA), the European Medicines Agency, Health Canada and the Therapeutic Goods Administration in Australia, for clinical application to patients 6-years and older carrying the G551D mutation which targets the molecular defect of the protein [14,15]. Login to comment 27 ABCC7 p.Gly551Asp Bompadre et al. [4] demonstrated that the G551D mutation abolishes the ATP-dependent gating of these channels, exhibiting only ATP-independent openings. Login to comment 28 ABCC7 p.Gly551Asp Not surprisingly, VX-770 potentiates G551D-CFTR activity by increasing the ATP-independent opening-rate and the open time [16,17]. Login to comment 63 ABCC7 p.Glu1371Ser We introduced the E1371S mutation, which abolishes ATPase activity [24], in WT and F508del-CFTR channels and expressed them in CHO cells. Login to comment 64 ABCC7 p.Glu1371Ser ABCC7 p.Glu1371Ser The duration of the locked-open time of the channels is calculated from the time- constants of F508del/E1371S and E1371S-CFTR current relaxations upon ATP withdrawal. Login to comment 66 ABCC7 p.Glu1371Ser ABCC7 p.Glu1371Ser The relaxation time constant increases about 60% for both F508del/E1371S and E1371S-CFTR, suggesting that the effect may not be specific to the mutant channel. Login to comment 68 ABCC7 p.Glu1371Ser When used in conjunction with 200 nM VX-770, the locked open time of F508del/E1371S channels can be further increased to 108 &#b1; 12 s (n = 14), a value Fig. 1. Effect of 200 nM VX-770 on temperature-corrected F508del-CFTR channels expressed in CHO cells. Login to comment 75 ABCC7 p.Glu1371Ser Here and below the dashed line represent the base line. similar to that of E1371S-CFTR channels in the absence of VX-770, indicating that VX-770 alone is not sufficient to fully restore the stability of the open-channel conformation of F508del channels when hydrolysis is abolished. Login to comment 110 ABCC7 p.Gly551Asp VX-770 has shown some efficacy in improving the lung-function of CF patients carrying the G551D mutation. Login to comment 111 ABCC7 p.Gly551Asp In vitro, it potentiates the activity of G551D-CFTR channels, a mutant that does not respond to ATP, by approximately 10 fold [14]. Login to comment 124 ABCC7 p.Glu1371Ser Representative traces for F508del/E1371S (A.) Login to comment 125 ABCC7 p.Glu1371Ser and E1371S (B.) Login to comment 128 ABCC7 p.Glu1371Ser C F508del/E1371S-CFTR current relaxation after 10 bc;M P-ATP + 200 nM VX-770 withdrawal and its exponential fit (green line) shown in comparison with representative fit for the relaxation after ATP + VX-770 (red line). Login to comment 129 ABCC7 p.Glu1371Ser ABCC7 p.Glu1371Ser D. summary of the effect of 200 nM VX-770 on the open time of F508del/E1371S and E1371S CFTR (n = 9-15). Login to comment