Tabcharani J A, Rommens J M, Hou Y X, Chang X B, Tsui L C, Riordan J R, Hanrahan J W
Department of Physiology, McGill University, Montréal, Québec, Canada.
Nature. 1993 Nov 4;366(6450):79-82. doi: 10.1038/366079a0.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a non-rectifying, low-conductance channel regulated by ATP and phosphorylation, which mediates apical chloride conductance in secretory epithelia and malfunctions in cystic fibrosis (CF). Mutations at Lys 335 and Arg 347 in the sixth predicted transmembrane helix of CFTR alter its halide selectivity in whole-cell studies and its single channel conductance, but the physical basis of these alterations is unknown and permeation in CFTR is poorly understood. Here we present evidence that wild-type CFTR can contain more than one anion simultaneously. The conductance of CFTR passes through a minimum when channels are bathed in mixtures of two permeant anions. This anomalous mole fraction effect can be abolished by replacing Arg 347 with an aspartate and can be toggled on or off by varying the pH after the same residue is replaced with a histidine. Thus the CFTR channel should provide a convenient model in which to study multi-ion pore behaviour and conduction. The loss of multiple occupancy may explain how naturally occurring CF mutations at this site cause disease.
囊性纤维化跨膜传导调节因子（CFTR）是一种由ATP和磷酸化调节的非整流性、低电导通道，它介导分泌上皮细胞顶端的氯离子传导，在囊性纤维化（CF）中功能异常。在CFTR预测的第六个跨膜螺旋中，赖氨酸335和精氨酸347处的突变在全细胞研究中改变了其卤化物选择性及其单通道电导，但这些改变的物理基础尚不清楚，并且对CFTR中的通透作用了解甚少。在此我们提供证据表明野生型CFTR可以同时容纳不止一个阴离子。当通道浸泡在两种通透阴离子的混合物中时，CFTR的电导会经过一个最小值。这种异常摩尔分数效应可以通过用天冬氨酸取代精氨酸347来消除，并且在用组氨酸取代相同残基后，通过改变pH值可以打开或关闭这种效应。因此，CFTR通道应该为研究多离子孔行为和传导提供一个便利的模型。多占据的丧失可能解释了该位点自然发生的CF突变如何导致疾病。
