Regulation of the CFTR channel by phosphorylation
Regulation of the CFTR channel by phosphorylation
复制标题
DOI：
10.1007/s004240100652
复制
发表时间：
2001-01-01
影响因子：
4.5
通讯作者：
Zhu, T
中科院分区：
文献类型：
--
作者：
Dahan, D;Evagelidis, A;Zhu, T
囊性纤维化跨膜传导调节剂（CFTR）氯离子通道受蛋白激酶和磷酸酶的紧密调控。CFTR的调控结构域约有20个位点可被蛋白激酶A （PKA）和C （PKC）磷酸化。这些位点数量如此之多的原因尚不清楚，但它们从鱼类到人类的保存表明它们在体内发挥着重要作用。PKA是一种重要的激活剂，PKC增强其对CFTR的刺激作用，其机制尚不完全清楚。CFTR对某些上皮细胞的生理刺激尚不清楚，其他丝氨酸/苏氨酸激酶甚至酪氨酸激酶也可能调节特定组织的CFTR。使CFTR失活的磷酸酶尚未在分子水平上得到明确的鉴定，然而，在几种细胞类型中，CFTR是由膜结合形式的蛋白磷酸酶2c （PP2C）调节的。通道分解的膜片钳研究、共免疫沉淀、化学交联研究和拉下试验都表明，CFTR和PP2C在一个稳定的调节复合物中密切相关。了解PP2C对CFTR的调控是一个优先事项，因为它有可能作为囊性纤维化治疗药物治疗的靶点。
Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels are regulated tightly by protein kinases and phosphatases. The regulatory domain of CFTR has about 20 potential sites for phosphorylation by protein kinases A (PKA) and C (PKC). The reason for this large number of sites is not known, however their conservation from fish to humans implies that they play important roles in vivo. PKA is an important activator, and its stimulation of CFTR is enhanced by PKC via mechanisms which are not fully understood. The physiological stimuli of CFTR are not known for some epithelia, and it appears likely that other serine/threonine and even tyrosine kinases also regulate CFTR in particular tissues. Phosphatases that deactivate CFTR have yet to be identified definitively at the molecular level, however CFTR is regulated by a membrane-bound form of protein phosphatase-2C (PP2C) in several cell types. Patch-clamp studies of channel rundown, coimmunoprecipitation, chemical cross-linking studies, and pull-down assays all indicate that CFTR and PP2C are closely associated within a stable regulatory complex. Understanding the regulation of CFTR by PP2C is a priority due to its potential as a target for pharmacotherapies in the treatment of cystic fibrosis.