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

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Author:: No author available

Journal Title:: ACTA PHYSIOLOGICA SINICA

Issue:: 4

DOI:: 10.3321/j.issn:0371-0874.2007.04.003

Key Word:: 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;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

Abstract： The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that forms a Cl- 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.

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