Martins Joana Raquel, Kongsuphol Patthara, Sammels Eva, Dahimène Shehrazade, Aldehni Fadi, Clarke Luka Alexander, Schreiber Rainer, de Smedt Humbert, Amaral Margarida D, Kunzelmann Karl
Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
Biochim Biophys Acta. 2011 Nov;1812(11):1385-92. doi: 10.1016/j.bbadis.2011.08.008. Epub 2011 Aug 30.
In many cells, increase in intracellular calcium (Ca(2+)) activates a Ca(2+)-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-CFTR, which is unable to exit the endoplasmic reticulum (ER). Since receptor-mediated Ca(2+) increase is Cl(-) dependent, we suggested that F508del-CFTR may function as an ER chloride counter-ion channel for Ca(2+). This was confirmed by expression of the double mutant F508del/G551D-CFTR, which remained in the ER but had no effects on Ca(2+). Moreover, F508del-CFTR could serve as a scavenger for inositol-1,4,5-trisphosphate [IP3] receptor binding protein released with IP(3) (IRBIT). Our data may explain how ER-localized F508del-CFTR controls intracellular Ca(2+) signaling.
在许多细胞中，细胞内钙（Ca(2+)）的增加会激活一种钙依赖性氯（Cl(-)）电导（CaCC）。在缺乏囊性纤维化跨膜电导调节因子（CFTR）介导的Cl(-)转运的囊性纤维化（CF）上皮细胞中，CaCC增强。在此，我们表明，在F508del纯合CF患者的新鲜分离的鼻上皮细胞中，TMEM16A和贝斯特罗芬1的表达未发生变化。然而，在诱导无法从内质网（ER）中排出的F508del-CFTR表达后，钙信号强烈增强。由于受体介导的Ca(2+)增加是Cl(-)依赖性的，我们推测F508del-CFTR可能作为Ca(2+)的内质网氯抗衡离子通道发挥作用。这通过双突变体F508del/G551D-CFTR的表达得到证实，该双突变体保留在内质网中但对Ca(2+)没有影响。此外，F508del-CFTR可以作为与肌醇-1,4,5-三磷酸[IP3]一起释放的IP3受体结合蛋白（IRBIT）的清除剂。我们的数据可能解释了内质网定位的F508del-CFTR如何控制细胞内Ca(2+)信号传导。
