VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.

ABSTRACT: VX-770 (ivacaftor) is approved for clinical use in CF patients bearing multiple CFTR mutations. VX-770 potentiated wildtype CFTR and several disease mutants expressed in oocytes in a manner modulated by PKA-mediated phosphorylation. Potentiation of some other mutants, including G551D-CFTR, was less dependent upon the level of phosphorylation, likely related to the severe gating defects in these mutants exhibited in part by a shift in PKA sensitivity to activation, possibly due to an electrostatic interaction of D551 with K1250. Phosphorylation-dependent potentiation of wildtype CFTR and other variants also was observed in epithelial cells. Hence, the efficacy of potentiators may be obscured by a ceiling effect when drug screening is performed under strongly phosphorylating conditions. Thes

SUBMITTER: Cui G 

PROVIDER: S-EPMC6749054 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature