Activation of G551D-CFTR by Bicyclooctane Compounds Is cAMP-dependent and Exhibits Low Sensitivity to Thiazolidinone CFTR Inhibitor CFTRinh-172  

作　　者：WANGYing ZHAOLu HECheng-yan XULi-na YANGHong 

机构地区：[1]MembraneChannelResearchLaboratory,NortheastNormalUniversity,Changchun130024,P.R.China [2]CollegeofTraditionalChineseMedicineMaterial,JilinAgriculturalUniversity,Changchun130118,P.R.China [3]China-JapanUnionHospital,JilinUniversity,Changchun130033,P.R.China.

出　　处：《Chemical Research in Chinese Universities》2005年第2期183-186,共4页高等学校化学研究（英文版）

基　　金：Start-upFundforReturnedOverseasScholarsfromNortheastNormalUniversity,NationalScienceFundforDistinguishedYoungScholars(No.30325011),DistinguishedYoungScholarsFundofJilinProvince(No.20030112),ExcellentYoungTeachersProgramofMinistryofEducation,P.R.China,theNationalNaturalScienceFoun-dationofChina(No.30470405)andtheNaturalScienceFoundationofJilinProvince(No.20010548and20030708).

摘　　要：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(G551D_ BCOs) with K_d down to 1 μmol/L. In this study, we analyzed the pharmacological activation of G551D-CFTR by the G551D_ BCOs by means of short circuit current analysis and cell-based fluorescence quenching assay. The G551D_ BCOs-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 G551D_ BCOs; (2) G551D_ BCOs and CFTRinh-172 may act at the same site on the G551D-CFTR molecule.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(G551D_ BCOs) with K_d down to 1 μmol/L. In this study, we analyzed the pharmacological activation of G551D-CFTR by the G551D_ BCOs by means of short circuit current analysis and cell-based fluorescence quenching assay. The G551D_ BCOs-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 G551D_ BCOs; (2) G551D_ BCOs and CFTRinh-172 may act at the same site on the G551D-CFTR molecule.

关 键 词：Cystic fibrosis(CF) Cystic fibrosis transmembrane conductance regulator(CFTR) Short circuit current analysis Pharmacological activation 

分 类 号：R977[医药卫生—药品] R596[医药卫生—药学]