Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC
Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC
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DOI：
10.1111/j.1469-7793.1998.825bp.x
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发表时间：
1998-05-01
影响因子：
5.5
通讯作者：
Kunzelmann, K
中科院分区：
文献类型：
--
作者：
Briel, M;Greger, R;Kunzelmann, K
1.当囊性纤维化跨膜传导调节因子（CFTR）被蛋白激酶A激活时，上皮Na+通道（ENaCs）被CFTR抑制。由于CFTR Cl-传导的cAMP依赖性激活在囊性纤维化（CF）中是有缺陷的，因此CFTR不抑制ENaC电流。这可以解释CF中发现的增强的Na+电导。在本研究中，我们研究了非洲爪蟾卵母细胞中共表达的CFTR和ENaC之间相互作用的可能机制.在共表达野生型或突变型CFTR和ENaC的卵母细胞中，由S-异丁基-1-甲基黄嘌呤（IBMX）激活的CFTR Cl-电流的大小决定了ENaC电流下调的程度.当细胞外Cl-被导电性差的阴离子（例如SCN-或葡萄糖酸盐）替代时，或者当CFTR被二苯胺羧酸盐（DPC，1 mmol l（-1））抑制时，CFTR抑制ENaC电流的能力显著降低。与负钳位电压相比，正钳位电压下ENaC的下调更明显。这表明外向电流，即Cl-通过激活CFTR的流入最有效地下调ENaC。1 μ mol l（-1）离子霉素对内源性Ca ~（2+）激活的Cl ~-电流的激活不抑制ENaC电流。这表明Cl-电流介导的ENaC抑制可能对CFTR具有特异性。目前的研究结果表明，CFTR下调ENaC与CFTR传导Cl-的能力相关。这些数据对CFTR被促分泌素激活时上皮细胞如何从NaCl吸收转换为NaCl分泌具有影响。
1. Epithelial Na+ channels (ENaCs) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is activated by protein kinase A. Since cAMP-dependent activation of CFTR Cl- conductance is defective in cystic fibrosis (CF), ENaC currents are not inhibited by CFTR. This could explain the enhanced Na+ conductance found in CF. In the present study, we examined possible mechanisms of interaction between CFTR and ENaC co-expressed in Xenopus oocytes.2. The magnitude of CFTR Cl- currents activated by S-isobutyl-1-methylxanthine (IBMX) in oocytes co-expressing either wild-type or mutant CFTR and ENaC determined the degree of downregulation of ENaC currents.3. The ability of CFTR to inhibit ENaC currents was significantly reduced either when extracellular Cl- was replaced by poorly conductive anions, e.g. SCN- or gluconate, or when CFTR was inhibited by diphenylamine-carboxylate (DPC, 1 mmol l(-1)).4. Downregulation of ENaC was more pronounced at positive when compared with negative clamp voltages. This suggests that outward currents, i.e. influx of Cl- through activated CFTR most effectively downregulated ENaC.5. Activation of endogenous Ca2+-activated Cl- currents by 1 mu mol l(-1) ionomycin did not inhibit ENaC current. This suggests that inhibition of ENaC mediated by Cl- currents may be specific to CFTR.6. The present findings indicate that downregulation of ENaC by CFTR is correlated to the ability of CFTR to conduct Cl-. The data have implications for how epithelia switch from NaCl absorption to NaCl secretion when CFTR is activated by secretagogues.