F508del-CFTR increases intracellular Ca2+ signaling that causes enhanced calcium-dependent Cl- conductance in cystic fibrosis
F508del-CFTR increases intracellular Ca2+ signaling that causes enhanced calcium-dependent Cl- conductance in cystic fibrosis
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DOI：
10.1016/j.bbadis.2011.08.008
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发表时间：
2011-11-01
影响因子：
6.2
通讯作者：
Kunzelmann, Karl
中科院分区：
文献类型：
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作者：
Martins, Joana Raquel;Kongsuphol, Patthara;Kunzelmann, Karl
在许多细胞中，细胞内钙（[Ca2+](i)）的增加激活了Ca2+依赖性氯离子（Cl-）电导（CaCC）。CaCC在缺乏Cl-转运的囊性纤维化（CF）上皮细胞中通过CF跨膜传导调节因子（CFTR）增强。本研究表明，在f508del纯合子CF患者新鲜分离的鼻上皮细胞中，TMEM16A和bestrophin 1的表达没有变化。然而，钙信号在诱导F508del-CF1'R表达后被强烈增强，而F508del-CF1'R无法退出内质网（ER）。由于受体介导的[Ca2+](i)增加是Cl-依赖的，我们认为F508del-CFTR可能是Ca2+的ER氯离子反离子通道。双突变体F508del/G551D-CFTR的表达证实了这一点，该突变体仍然存在于内质网中，但对[Ca2+]没有影响；此外，F508del-CFTR还可以作为IP3释放的肌醇-1,4,5-三磷酸[IP3]受体结合蛋白（IRBIT）的清道夫。我们的数据可以解释内质网定位的F508del-CFTR如何控制细胞内Ca2+信号。(C) 2011 Elsevier B.V.版权所有
In many cells, increase in intracellular calcium ([Ca2+](i)) activates a Ca2+-dependent chloride (Cl-) conductance (CaCC). CaCC is enhanced in cystic fibrosis (CF) epithelial cells lacking Cl- transport by the CF transmembrane conductance regulator (CFTR). Here, we show that in freshly isolated nasal epithelial cells of F508del-homozygous CF patients, expression of TMEM16A and bestrophin 1 was unchanged. However, calcium signaling was strongly enhanced after induction of expression of F508del-CF1'R, which is unable to exit the endoplasmic reticulum (ER). Since receptor-mediated [Ca2+](i) increase is Cl- dependent, we suggested that F508del-CFTR may function as an ER chloride counter-ion channel for Ca2+. This was confirmed by expression of the double mutant F508del/G551D-CFTR, which remained in the ER but had no effects on [Ca2+];. Moreover, F508del-CFTR could serve as a scavenger for inositol-1,4,5-trisphosphate [IP3] receptor binding protein released with IP3 (IRBIT). Our data may explain how ER-localized F508del-CFTR controls intracellular Ca2+ signaling. (C) 2011 Elsevier B.V. All rights reserved.