对羟基苯甲酸丁酯激活囊性纤维化跨膜电导调节因子氯离子通道开放

Butyl-p-hydroxybenzoate stimulates cystic fibrosis transmembrane conductance regulator Cl^- transport

对20种挥发油类化合物中的对羟基苯甲酸丁酯(butyl-p-hydroxybenzoate,Bpb)的CFTR氯离子通道激活作用进行系统的分子药理学研究。利用稳定共表达人CFTR和对卤族元素碘离子高度敏感的荧光绿蛋白突变体(EYFP)的Fischer大鼠甲状腺(FRT)上皮细胞为筛选模型,测定Bpb对CFTR介导的I-内流速度的影响。发现了Bpb对野生型CFTR的Cl-通道具有显著的激活作用;Bpb不能纠正△F508-CFTR蛋白胞内转运的障碍,但却具有纠正其通道开放障碍的功能;Bpb对G551D突变型CFTRCl-通道无激活作用。激活作用具有可逆和剂量依赖的特点,初步机制分析结果表明,它可能是通过与CFTR直接结合而发挥作用的。首次发现了Bpb对CFTRCl-通道有激活作用,为深入研究Bpb的药理学作用提供了新方向,使其有可能成为治疗CFTR有关疾病的先导药物。

This study is to investigate the activation effect of butyl-p-hydroxybenzoate （Bpb） on cAMP-dependent cystic fibrosis transmembrane conductance regulator （CFTR） chloride chainnel gating. A stably transfected Fischer rat thyroid （FRT） epithelial cell lines co-expressing human CPTR and a green fluorescent protein mutant with ultra-high halide sensitivity （EYFP） were used to measure CFTR-mediated iodide influx rates. Bpb was identified as an effective activator of wild-type CFTR chloride channel, it can correct △F508-CPTR gating defects but not processing defect. Bpb can＇t potentiate G551D-CFTR channel gating. The activity was reversible and dose-dependent. The study also provided clues that Bpb activates CFTR chloride channel through a direct binding mechanism. Our study identified Bpb as a novel structure CFTR activator. Bpb may be useful for probing CFTR channel gating mechanisms and as a lead compound to develop pharmacological therapy for CFTR-related disease.