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The Molecular Basis of Chloride Channel Dysregulation in Cystic Fibrosis
Author(s) -
DE JONGE H. R.
Publication year - 1989
Publication title -
acta paediatrica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.772
H-Index - 115
eISSN - 1651-2227
pISSN - 0803-5253
DOI - 10.1111/apa.1989.78.s363.14
Subject(s) - chloride channel , protein kinase a , cystic fibrosis transmembrane conductance regulator , diacylglycerol kinase , microbiology and biotechnology , second messenger system , phosphorylation , apical membrane , kinase , phosphoprotein , biochemistry , intracellular , biology , protein kinase c , membrane , gene
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.