Activation of G551D-CFTR by Bicyclooctane Compounds Is cAMP-dependent and Exhibits Low Sensitivity to Thiazolidinone CFTR Inhibitor CFTRinh-172 |
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Authors: | WANG Ying ZHAO Lu HE Cheng-Yan XU Li-na YANG Hong |
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Institution: | 1. Membrane Channel Research Laboratory, Northeast Normal University, Changchun 130024, P. R. China;
2. College of Traditional Chinese Medicine Material, Jilin Agricultural University, Changchun 130118, P.R. China;
3. China-Japan Union Hospital, Jilin University, Changchun 130033, P.R. China |
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Abstract: | The G551D-CFTR mutation causing cystic fibrosis (CF) results from a missense mutation at codon 551(G551D) in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR). The G551D mutation in CFTR results in a reduced functional channel but G551D-CFTR is appropriately inserted in the apical membrane. In previous studies we discovered a class of high-affinity bicyclooctane (BCO)G551D-CFTR activators(G551DBCOs) with Kd down to 1μmol/L. In this study, we analyzed the pharmacological activation of G551D-CFTR by the G551DBcos by means of short circuit current analysis and cell-based fluorescence quenching assay. The G551DBCOs-induced G551D-CFTR activation is cAMP-dependent and is less sensitive to thiazolidinone CFTR inhibitor CFTRinh-172. These data suggest that (1) the phosphorylation of G551D-CFTR by protein kinase A is required for the activation by G551DBcos; (2) G551DBCos and CFTRinh-172 may act at the same site on the G551D-CFTR molecule. |
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Keywords: | Cystic fibrosis(CF) Cystic fibrosis transmembrane conductance regulator(CFTR) Short circuit current analysis Pharmacological activation |
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