Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models

Item Type:	Article
Title:	Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models
Creators Name:	Zdebik, A.A. and Cuffe, J.E. and Bertog, M. and Korbmacher, C. and Jentsch, T.J.
Abstract:	Cystic fibrosis is a fatal inherited disease that is caused by mutations in the gene encoding a cAMP-activated chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). It has been suggested that the cystic fibrosis phenotype might be modulated by the presence of other Cl(-) channels that are coexpressed with CFTR in some epithelial cells. Because the broadly expressed plasma membrane Cl(-) channel, ClC-2, is present in the tissues whose function is compromised in cystic fibrosis, we generated mice with a disruption of both Cl(-) channel genes. No morphological changes in their intestine, lung, or pancreas, tissues affected by cystic fibrosis, were observed in these mice. The mortality was not increased over that observed with a complete lack of functional CFTR. Surprisingly, mice expressing mutant CFTR (deletion of phenylalanine 508), survived longer when ClC-2 was disrupted additionally. Currents across colonic epithelia were investigated in Ussing chamber experiments. The disruption of ClC-2, in addition to CFTR, did not decrease Cl(-) secretion. Colon expressing wild-type CFTR even secreted more Cl(-) when ClC-2 was disrupted, although CFTR transcript levels were unchanged. It is concluded that ClC-2 is unlikely to be a candidate rescue channel in cystic fibrosis. Our data are consistent with a model in which ClC-2 is located in the basolateral membrane.
Keywords:	Cell Membrane, Chloride Channels, Colon, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Animal Disease Models, Epithelium, Heterozygote, Biological Models, Mutation, Pancreas, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Animals, Mice
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	279
Number:	21
Page Range:	22276-22283
Date:	21 May 2004
Official Publication:	https://doi.org/10.1074/jbc.M309899200
PubMed:	View item in PubMed

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