川陈皮素对囊性纤维化跨膜传导调节因子的激活作用

杨 爽; 于 波; 张耀方; 王 雪; 杨 红

川陈皮素对囊性纤维化跨膜传导调节因子的激活作用

The activation effect of nobiletin on cystic fibrosis transmembrane conductance regulator chloride channel

摘要

摘要:
本实验利用荧光淬灭实验和膜片钳技术在稳定表达人CFTR和荧光绿蛋白突变体EYFP/H148Q的Fischer大鼠甲状腺上皮细胞 (Fischer rat thyroid, FRT) 上, 测定川陈皮素 (nobiletin) 对囊性纤维化跨膜传导因子 (cystic fibrosis transmembrane conductance regulator, CFTR) 氯离子通道的激活作用。结果发现, 川陈皮素以剂量依赖的方式激活CFTR氯离子通道的Cl^－转运活性, 且这种活性是快速、可逆的, 并能够被CFTR特异性抑制剂CFTR_inh-172完全抑制。初步的分子机制研究表明, 川陈皮素是以与CFTR直接作用来激活通道活性的。进一步的研究结果显示, 川陈皮素能够有效刺激小鼠气管黏膜下腺液体分泌速度。因此, 川陈皮素可能发展成为治疗包括支气管扩张在内的CFTR相关疾病的先导药物。

Abstract:
Aim of the present study is to investigate activation effect of nobiletin on cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity. CFTR-mediated iodide influx assay and patch-clamp tests were done on FRT cells stably co-transfected with human CFTR and EYFP/H148Q. Nobiletin potently activated CFTR chloride channel activity in a dose- and time-dependent manner. The CFTR blocker CFTR_inh-172 could completely reverse the effect. Preliminary mechanism study indicated that nobiletin activated CFTR chloride channel through a direct binding way. In addition, ex vivo tests done on mice trachea showed that nobiletin time-dependently stimulated submucosal gland fluid secretion. Nobiletin may be a therapeutic lead compound in treating CFTR-related diseases including disseminated bronchiectasis.

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