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The Molecular Basis of Chloride Channel Dysregulation in Cystic Fibrosis

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The opening and closing of chloride (Cl) channels in the apical membrane of epithelial cells is regulated by hormones, neurotransmitters and enterotoxins (intestine) acting through a variety of intracellular messengers, including cyclic nucleotides (cAMP, cGMP), calcium (Ca) and diacylglycerol (DAG). The chloride impermeability of epithelial membranes observed in cystic fibrosis (CF) patients does not result from a defect in the Cl conducting properties of the channel or in channel recruitment but stems either from a defect in a key regulator of the channel, presumably a phosphoprotein, or from the hyperactivation of a channel closing mechanism, presumably a protein phosphatase or a down‐regulating protein kinase (i.e. protein kinase C). In vitro phosphorylation of isolated intestinal brush border membranes has revealed the existence of a 25000 molecular weight proteolipid (p25) acting as a cosubstrate for both cGMP‐ and cAMP‐dependent protein kinases and cross‐reacting with antibodies directed against the cytoplasmic tail of the band 3 anion exchanger from erythrocytes. The putative role of p25 in Cl channel regulation and its relationship to an unidentified GTP‐binding protein recently implicated in Cl channel activation is discussed on the basis of a regulatory model indicating potential sites of the CF defect at a molecular level.
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Keywords: chloride channel; cystic fibrosis; intestinal epithelium; phosphorylation; protein kinase; regulatory defect

Document Type: Research Article

Affiliations: From the Department of Biochemistry I, Medical Faculty, Erasmus University, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

Publication date: November 1, 1989

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