Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models.
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.
Zdebik
Anselm A
AA
Zentrum für Molekulare Neurobiologie (ZMNH), Falkenried 94, D-20246 Hamburg, Germany.
Cuffe
John E
JE
Bertog
Marko
M
Korbmacher
Christoph
C
Jentsch
Thomas J
TJ
D000818:Animals; D000090007:CLC-2 Chloride Channels; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism*; D003106:Colon / Q000473:pathology; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator