期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 588, 期 8, 页码 1211-1225出版社
WILEY
DOI: 10.1113/jphysiol.2009.180224
关键词
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资金
- ELAN-Fonds
- Johannes and Frieda Marohn-Stiftung
- Deutsche Forschungsgemeinschaft (DFG) [SFB423]
- Alphonse and Jean Forton Fund - Koning Boudewijn Stichting [2005 04 R7 115 BO, 2008-R10150-002]
- Het Fonds voor Wetenschappelijk Onderzoek Vlaanderen [G.0521.06, 1.5.111.07]
Increased activity of the epithelial sodium channel (ENaC) in the respiratory airways contributes to the pathophysiology of cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In some patients suffering from atypical CF a mutation can be identified in only one CFTR allele. We recently identified in this group of CF patients a heterozygous mutation (W493R) in the alpha-subunit of ENaC. Here, we investigate the functional effects of this mutation by expressing wild-type alpha beta gamma ENaC or mutant alpha(W493R)beta gamma ENaC in Xenopus oocytes. The alpha W493R mutation stimulated amiloride-sensitive whole-cell currents (delta I-ami) by similar to 4-fold without altering the single-channel conductance or surface expression of ENaC. As these data suggest that the open probability (P-o) of the mutant channel is increased, we investigated the proteolytic activation of ENaC by chymotrypsin. Single-channel recordings revealed that chymotrypsin activated near-silent channels in outside-out membrane patches from oocytes expressing wild-type ENaC, but not in membrane patches from oocytes expressing the mutant channel. In addition, the alpha W493R mutation abolished Na+ self inhibition of ENaC, which might also contribute to its gain-of-function effects. We conclude that the alpha W493R mutation promotes constitutive activation of ENaC by reducing the inhibitory effect of extracellular Na+ and decreasing the pool of near-silent channels. The resulting gain-of-function phenotype of the mutant channel might contribute to the pathophysiology of CF in patients carrying this mutation.
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