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囊性纤维化跨膜转运调节体氯离子通道-----跨上皮离子转运的多功能引擎

李红宇, 蔡志伟, 陈正豪, 鞠敏, 徐喆, Sheppard D N

布里斯托大学医学科学院生理系,布里斯托BS8 1TD；美国

摘要

囊性纤维化跨膜转运调节体（cystic fibrosis transmembrane conductance regulator，CFTR）是ATP结合转运体超家族（ATP--binding cassette transporter superfamily）的一名特殊成员，因为它是一个具有相当复杂调控机制的氯离子通道。CFTR由五个结构域（domain）组成：两个跨膜结构域（membrane--spanning domains，MSDs），两个核苷酸结合域（nucleotide--binding domains．NBDs）和一个特殊的调控域（regulatory domain，RD）。MSDs构成一个低电导（6---12pS）的阴离子选择性孔道（pore），其形状如同不对称的沙漏，胞外小胞内大，狭窄部分为离子筛。两个NBDs组成头尾相对的二聚体，在二聚体之间的接触面上有两个能和ATP结合的位点（位点1和位点2）。CFTR的门控机制是：ATP分子与位点1和2相互作用促使NBD二聚体的结合与解离，从而引起MSDs的构象发生变化进而使通道孔打开和关闭。RD具有多样化的结构，它含有多个磷酸化共有位点（consensus　phosphorylation　sites）。RD的磷酸化促进NBDs与ATP的结合，从而使CFTR得以激活。CFTR通过支架蛋白与其它膜受体以及蛋白激酶、磷酸酶形成大分子信号复合体。在复杂的细胞信号系统参与下，CFTR的功能活动在时间和空间上得到精确的调控。此外，CFTR的活动与细胞代谢有紧密联系：CFTR与代谢酶形成大分子复合体，当细胞能量需求增加时，CFTR活动会受到抑制而使细胞能量得以保存。CFTR广泛分布于机体上皮组织，它通过促进水盐转运而控制上皮细胞分泌物的量与组成。值得注意的是，在呼吸道，CFTR还对机体的防御机制起重要作用。CFTR功能失常严重影响跨上皮离子转运，进而引起或加重某些疾病。

关键词： ATP结合转运体超家族; 囊性纤维化跨膜转运调节体; 囊性纤维化跨膜转运调节体相互作用蛋白; 囊性纤维; 化跨膜转运调节体相关疾病; 囊性纤维化病; 氯离子通道; 跨上皮离子转运; 大分子信号复合体; 分泌性腹泻

The cystic fibrosis transmembrane conductance regulator Cl~(-) channel： a versatile engine for transepithelial ion transport

Li Hongyu, Cai Zhiwei, Chen Jenghaur, Ju Min, Xu Zhe, Sheppard D N

Department of Physiology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 ITD；USA

Abstract

The cystic fibrosis transmembrane conductance regulator （CFTR） is a unique member of the ATP-binding cassette （ABC） transporter superfamily that forms a CI^- channel with complex regulation. CFTR is composed of five domains： two membrane-spanning domains （MSDs）, two nucleotide-binding domains （NBDs） and a unique regulatory domain （RD）. The MSDs assemble to form a low conductance （6-10 pS） anion-selective pore with deep intracellular and shallow extracellular vestibules separated by a selectivity filter. The NBDs form a head-to-tail dimer with two ATP-binding sites （termed sites 1 and 2） located at the dimer interface. Anion flow through CFTR is gated by the interaction of ATP with sites 1 and 2 powering cycles of NBD dimer association and dissociation and hence, conformational changes in the MSDs that open and close the channel pore. The RD is an unstructured domain with multiple consensus phosphorylation sites, phosphorylation of which stimulates CFTR function by enhancing the interaction of ATP with the NBDs, Tight spatial and temporal control of CFTR activity is achieved by＂ macromolecular signalling complexes in which scaffolding proteins colocalise CFTR and plasma membrane receptors with protein kinases and phosphatases. Moreover, a macromolecular complex composed of CFTR and metabolic enzymes （a CFTR metabolon） permits CFTR activity to be coupled tightly to metabolic pathways within cells so that CFTR inhibition conserves vital energy stores. CFTR is expressed in epithelial tissues throughout the body, lining ducts and tubes. It functions to control the quantity and composition of epithelial secretions by driving either the absorption or secretion of salt and water. Of note, in the respiratory airways CFTR plays an additional important role in host defence. Malfunction of CFTR disrupts transepithelial ion transport leading to a wide spectrum of human disease.

Key words: ATP-binding cassette transporter;cystic fibrosis transmembrane conductance regulator （CFTR）;CFTR interacting proteins;CFTR-opathies;cystic fibrosis;chloride ion channel;epithelial ion transport;macromolecular signalling complex;secretory diarrhoea ;

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引用本文：

李红宇, 蔡志伟, 陈正豪, 鞠敏, 徐喆, Sheppard D N. 囊性纤维化跨膜转运调节体氯离子通道-----跨上皮离子转运的多功能引擎[J]. 生理学报 2007; 59 (4): 416-430.

Li Hongyu, Cai Zhiwei, Chen Jenghaur, Ju Min, Xu Zhe, Sheppard D N. The cystic fibrosis transmembrane conductance regulator Cl~(-) channel： a versatile engine for transepithelial ion transport. Acta Physiol Sin 2007; 59 (4): 416-430 (in Chinese with English abstract).