DEFECTIVE REGULATION OF OUTWARDLY RECTIFYING CL- CHANNELS BY PROTEIN KINASE-A CORRECTED BY INSERTION OF CFTR
DEFECTIVE REGULATION OF OUTWARDLY RECTIFYING CL- CHANNELS BY PROTEIN KINASE-A CORRECTED BY INSERTION OF CFTR
复制标题
DOI：
10.1038/358581a0
复制
发表时间：
1992-08-13
期刊：
影响因子：
64.8
通讯作者：
GUGGINO, WB
中科院分区：
文献类型：
--
作者：
EGAN, M;FLOTTE, T;GUGGINO, WB
囊性纤维化（CF）是一种致命的遗传性疾病，可导致Cl-渗透性降低1、粘液硫酸化增加2、Na+吸收增加3和溶酶体囊泡酸化缺陷4。CF基因编码一种蛋白质（囊性纤维化跨膜电导调节因子，CFTR 5），可作为具有线性电流-电压关系的低电导Cl-通道发挥作用，其调节在CF患者中存在缺陷6 -8。较大的电导，外向整流氯离子通道也有缺陷的CF和未能激活时，暴露于环AMP依赖性蛋白激酶A或蛋白激酶C9-13。外向整流氯离子通道在CF中的作用受到质疑14。我们在这里报告，表达重组CF基因使用腺相关病毒载体在CF支气管上皮细胞纠正缺陷的Cl-分泌，它诱导的外观小，线性电导Cl-通道，并恢复蛋白激酶A激活外向整流Cl-通道。这些结果重新确立了CF中外向整流Cl-通道的参与，并表明CFTR调节气道组织中不止一种传导途径。
CYSTIC fibrosis (CF) is a lethal genetic disease resulting in a reduced Cl- permeability1, increased mucous sulphation2, increased Na+ absorption3 and defective acidification of lysosomal vesicles4. The CF gene encodes a protein (the cystic fibrosis transmembrane conductance regulator, CFTR5) that can function as a low-conductance Cl- channel with a linear current-voltage relationship whose regulation is defective in CF patients6-8. Larger conductance, outwardly rectifying Cl- channels are also defective in CF and fail to activate when exposed either to cyclic AMP-dependent protein kinase A or to protein kinase C9-13. The role of the outwardly rectifying Cl- channel in CF has been questioned14. We report here that expression of recombinant CF genes using adeno-associated virus vectors in CF bronchial epithelial cells corrects defective Cl- secretion, that it induces the appearance of small, linear conductance Cl- channels, and restores protein kinase A activation of outwardly rectifying Cl- channels. These results re-establish an involvement of outwardly rectifying Cl- channels in CF and suggest that CFTR regulates more than one conductance pathway in airway tissues.