Abstract
The protein defective in cystic fibrosis (CF), the CF transmembrane-conductance regulator (CFTR), functions as an epithelial chloride channel and as a regulator of separate ion channels. Although the consequences that disease-causing mutations have on the chloride-channel function have been studied extensively, little is known about the effects that mutations have on the regulatory function. To address this issue, we transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens, and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain (NBD1), DeltaF508, functioned as a chloride channel but did not regulate ORCCs. However, CFTR bearing disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
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Amino Acid Substitution / genetics
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Binding Sites
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Cell Line
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Chloride Channels / antagonists & inhibitors
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Chloride Channels / metabolism*
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Chlorides / metabolism
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Cyclic AMP / metabolism
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Cystic Fibrosis / genetics*
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Cystic Fibrosis / physiopathology
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Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
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Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
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Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
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Electric Conductivity
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Glyburide / pharmacology
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Glycosylation
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Humans
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Male
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Molecular Weight
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Mutation / genetics*
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Mutation, Missense / genetics
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Phenotype
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Vas Deferens / abnormalities*
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Vas Deferens / metabolism
Substances
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CFTR protein, human
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Chloride Channels
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Chlorides
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Recombinant Proteins
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Cystic Fibrosis Transmembrane Conductance Regulator
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Cyclic AMP
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
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Glyburide