Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis
Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis
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DOI：
10.1038/35065099
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发表时间：
2001-03-01
期刊：
影响因子：
64.8
通讯作者：
Muallem, S
中科院分区：
文献类型：
--
作者：
Choi, JY;Muallem, D;Muallem, S
囊性纤维化（CF）是一种由囊性纤维化跨膜电导调节因子（CFTR）突变引起的疾病。最初，发现 CF1 中汗管中的 Cl- 电导受损，这一发现已扩展到所有表达 CFTR 的细胞 (2-4)。随后对该基因 (5,6) 的克隆表明 CFTR 作为环 AMP 调节的 Cl- 通道发挥作用 (7)；一些 CF 引起的突变会抑制 CFTR Cl 通道活性 (2-4,8)。然而，具有正常 Cl 通道活性的其他 C 致病突变体的鉴定表明，其他 CFTR 依赖性过程导致了该疾病。事实上，CFTR 调节其他转运蛋白 (3,4)，包括 Cl- 偶联的 HCO3- 转运 (9,10)。碱性液体由正常组织分泌，而酸性液体由表达突变 CFTR 的组织分泌(11)，表明此活性的重要性。 HCO3- 和 pH 影响粘蛋白粘度 (12,13) 和细菌结合 (14,15)。我们已经检查了 CFTR 突变体的 Cl- 偶联 HCO3- 转运，这些突变体保留了大量或正常的 Cl- 通道活性。在这里，我们表明，据报道与胰腺功能不全的 CF 相关的突变体不支持 HCO3- 转运，而与胰腺功能充足相关的突变体则显示出 HCO3- 转运减少。我们的研究结果证明了 HCO3- 转运在分泌上皮细胞功能和 CF 中的重要性。
Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF1, a finding that has been extended to all CFTR-expressing cells(2-4). Subsequent cloning of the gene(5,6) showed that CFTR functions as a cyclic-AMP-regulated Cl- channel(7); and some CF-causing mutations inhibit CFTR Cl- channel activity(2-4,8). The identification of additional C-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters(3,4), including Cl- -coupled HCO3- transport(9,10). Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues(11), indicating the importance of this activity. HCO3- and pH affect mucin viscosity(12,13) and bacterial binding(14,15). We have examined Cl- -coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO3- transport, and those associated with pancreatic sufficiency show reduced HCO3- transport. Our findings demonstrate the importance of HCO3- transport in the function of secretory epithelia and in CF.