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高等学校化学研究 ›› 2005, Vol. 21 ›› Issue (2): 183-186.

• Articles • 上一篇    下一篇

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

WANG Ying1, ZHAO Lu2, HE Cheng-yan3, XU Li-na1, YANG Hong1   

  1. 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
  • 收稿日期:2004-09-24 出版日期:2005-03-24 发布日期:2011-07-27
  • 基金资助:

    Supported by Start-up Fund for Returned Overseas Scholars from Northeast Normal University, National Science Fund for Distinguished Young Scholars (No.30325011), Distinguished Young Scholars Fund of Jilin Province (No.20030112), Excellent Young Teachers Program of Ministry of Education, P.R.China, the National Natural Science Foundation of China(No.30470405) and the Natural Science Foundation of Jilin Province(No.20010548 and 20030708).

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

WANG Ying1, ZHAO Lu2, HE Cheng-yan3, XU Li-na1, YANG Hong1   

  1. 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
  • Received:2004-09-24 Online:2005-03-24 Published:2011-07-27
  • Supported by:

    Supported by Start-up Fund for Returned Overseas Scholars from Northeast Normal University, National Science Fund for Distinguished Young Scholars (No.30325011), Distinguished Young Scholars Fund of Jilin Province (No.20030112), Excellent Young Teachers Program of Ministry of Education, P.R.China, the National Natural Science Foundation of China(No.30470405) and the Natural Science Foundation of Jilin Province(No.20010548 and 20030708).

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被引次数

2

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(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.

关键词: Cystic fibrosis(CF), Cystic fibrosis transmembrane conductance regulator(CFTR), Short circuit current analysis, Pharmacological activation

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.

Key words: Cystic fibrosis(CF), Cystic fibrosis transmembrane conductance regulator(CFTR), Short circuit current analysis, Pharmacological activation