Billet Arnaud, Hanrahan John W
J. W. Hanrahan: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6.
J Physiol. 2013 Nov 1;591(21):5273-8. doi: 10.1113/jphysiol.2013.261909. Epub 2013 Aug 19.
cAMP-stimulated anion conductance is defective in cystic fibrosis (CF). The regulatory domain of CFTR, the anion channel protein encoded by the CF gene, possesses an unusually high density of consensus sequences for phosphorylation by protein kinase A (14 in a stretch of <200 amino acids). Thus it is not surprising that CFTR is viewed primarily as a cAMP-stimulated anion channel, and most studies have focused on this mode of activation. However, there is growing evidence that CFTR also responds to Ca(2+)-mobilizing secretagogues and contributes substantially to cholinergic and purinergic responses in native tissues. G protein-coupled receptors that signal through Gαq can stimulate CFTR channels by activating Ca(2+)-dependent adenylyl cyclase and tyrosine kinases, and also by inhibiting protein phosphatase type 2A. Here we review evidence for these novel mechanisms of CFTR activation and discuss how they may help explain previous observations.
在囊性纤维化（CF）中，环磷酸腺苷（cAMP）刺激的阴离子传导存在缺陷。CF基因编码的阴离子通道蛋白CFTR的调节结构域具有异常高的蛋白激酶A磷酸化共有序列密度（在一段<200个氨基酸的序列中有14个）。因此，CFTR主要被视为一种cAMP刺激的阴离子通道也就不足为奇了，并且大多数研究都集中在这种激活模式上。然而，越来越多的证据表明，CFTR也对动员钙离子的促分泌剂有反应，并在天然组织的胆碱能和嘌呤能反应中起重要作用。通过Gαq信号传导的G蛋白偶联受体可以通过激活钙依赖性腺苷酸环化酶和酪氨酸激酶，以及通过抑制2A型蛋白磷酸酶来刺激CFTR通道。在这里，我们综述了这些CFTR激活新机制的证据，并讨论它们如何有助于解释先前的观察结果。
