Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant Delta F508-CFTR

Kate J. Treharne, Zhe Xu, Jeng-Haur Chen, O. Giles Best, Diane M. Cassidy, Dieter C. Gruenert, Peter Hegyi, Michael A. Gray, David N. Sheppard, Karl Kunzelmann, Anil Mehta

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    Abstract

    Background: Deletion of phenylalanine-508 (Delta F508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between Delta F508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl- transport, closing wtCFTR in cellattached membrane patches. CK2 and wtCFTR coprecipitate and CK2 co-localized with wtCFTR (but not Delta F508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and Delta F508-CFTR expressing oocytes, only Delta F508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the Delta F508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not Delta F508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by Delta F508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR. Copyright (C) 2009 S. Karger AG, Basel

    Original languageEnglish
    Pages (from-to)347-360
    Number of pages14
    JournalCellular Physiology and Biochemistry
    Volume24
    Issue number5-6
    DOIs
    Publication statusPublished - 2009

    Keywords

    • ATP-binding cassette transporter
    • CFTR
    • Chloride ion channel
    • Channel regulation
    • Cystic fibrosis
    • Protein kinase CK2
    • TRANSMEMBRANE-CONDUCTANCE-REGULATOR
    • PANCREATIC-DUCT CELLS
    • BRONCHIAL EPITHELIAL-CELLS
    • POLYAMINE METABOLISM
    • CHAPERONE CALNEXIN
    • CHLORIDE CHANNEL
    • INTRACELLULAR PH
    • FLUID SECRETION
    • PLASMA-MEMBRANE
    • HCO3-SECRETION

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