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These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.

Misfolding of cystic fibrosis transmembrane conductance regulator protein (CFTR) causes the fatal lung disease cystic fibrosis. VX-809 was developed to suppress disease-related folding defects in CFTR. VX-809 suppresses folding defects in CFTR by modulating the conformation of membrane-spanning domain 1. VX-808 is thereby able to partially restore function to F508del-CFTR and other disease-related mutants.

These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.

A cDNA for a rat vesicular monoamine transporter, desgatd MAT, was isolated by expression cloning in a mammalian cell line (CV-1). (1-4). The biogenic amine Na+-dependent transporters (reuptake transporters) located at the plasma membrane are responsible for transport of the released monoamines back into the cytoplasm, where they may be repackaged by the vesicular transporter into storage organelles or degraded by monoamine oxidases (5, 6).Several distinguishing features of the MAT are as follows: (i) broad selectivity for 5-hydroxytryptamine (serotonin) (5HT), dopamine (DA), and norepinephrine (NE) uptake, (ii) specific inhibition of transport by reserpine (RES) and tetrabenazine (TBZ), and (iii) transmembrane H+-electrochemical dependence of monoamine accumulation (1-4) .

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A complementary DNA clone for a serotonin (5HT) transporter has been isolated from rat basophilic leukemia cells. The complementary DNA sequence predicts a 653-amino acid protein with 12 to 13 putative transmembrane domains. The 5HT transporter has significant homology to the gamma-aminobutyric acid, dopamine, and norepinephrine transporters. Uptake by CV-1 cells expressing the transporter complementary DNA resembles 5HT uptake by platelets and brain synaptosomes; it is sensitive to antidepressants, amphetamine derivatives, and cocaine.

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