Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium
Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium
复制标题
环磷酸腺苷依赖性蛋白激酶在正常而非囊性纤维化气道上皮中打开氯离子通道
作者：
Ming Li;J. D. McCann;Carole M. Liedtket;A. Nairn;P. Greengard;M. Welsh
气道上皮分泌的氯（Cl-）部分调节呼吸道液体的数量和组成，从而促进粘膜纤毛清除。Cl-分泌速率由顶端膜Cl-通道控制1。顶端Cl-通道被打开，Cl-分泌被各种激素和神经递质刺激，增加细胞内环AMP（cAMP）1-2的水平。在囊性纤维化（CF）中，一种常见的白人致死性遗传疾病，气道3，4，汗腺导管5，分泌线圈6和可能的其他上皮7是阴离子不可渗透的。这种异常可以解释该疾病的几种临床表现。CF-气道上皮中的Cl-不渗透性已定位于顶端细胞膜4，其中Cl-通道的调节是异常的8，9：激素促分泌素适当地刺激cAMP积累，但Cl-通道未能打开。在这里，我们报告说，纯化的催化亚基cAMP依赖性蛋白激酶加上ATP开放Cl-通道在切除，无细胞补丁的膜从正常细胞，但未能打开Cl-通道CF细胞。这些结果表明，在正常细胞中，cAMP依赖性蛋白激酶磷酸化Cl-通道或相关的调节蛋白，导致通道开放。CF Cl-通道未能打开表明通道或相关调节蛋白存在缺陷。
Chloride (Cl–) secretion by the airway epithelium regulates, in part, the quantity and composition of the respiratory tract fluid, thereby facilitating mucociliary clearance. The rate of Cl– secretion is controlled by apical membrane Cl– channels1. Apical Cl– channels are opened and Cl– secretion is stimulated by a variety of hormones and neurotransmitters that increase intracellular levels of cyclic AMP (cAMP)1–2. In cystic fibrosis (CF), a common lethal genetic disease of Caucasians, airway3,4, sweat-gland duct5, secretory-coil6 and possibly other epithelia7 are anion impermeable. This abnormality may explain several of the clinical manifestations of the disease. The Cl– impermeability in CF-airway epithelia has been localized to the apical cell membrane4, where regulation of Cl– channels is abnormal8,9: hormonal secretagogues stimulate cAMP accumulation appropriately but Cl– channels fail to open. Here we report that the purified catalytic subunit of cAMP-dependent protein kinase plus ATP opens Cl– channels in excised, cell-free patches of membrane from normal cells, but fails to open Cl–; channels in CF cells. These results indicate that in normal cells, the cAMP-dependent protein kinase phosphorylates the Cl– channel or an associated regulatory protein, causing the channel to open. The failure of CF Cl– channels to open suggests a defect either in the channel or in such an associated regulatory protein.
通过气道上皮细胞输送电解质。
影响因子：
33.6
作者：
Welsh,MJ
通讯作者：
Welsh,MJ
DOI：
10.1126/science.2424085
发表时间：
1986
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Welsh,MJ
通讯作者：
Welsh,MJ
囊性纤维化降低了气管上皮细胞培养的单层细胞的顶膜氯离子渗透性。
DOI：
10.1073/pnas.82.18.6167
发表时间：
1985
影响因子：
11.1
作者：
Widdicombe,JH;Welsh,MJ;Finkbeiner,WE
通讯作者：
Finkbeiner,WE