Inhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant Δf508-CFTR

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

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Abstract

Background: Deletion of phenylalanine-508 (ΔF508) 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 ΔF508-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 cell-attached membrane patches. CK2 and wtCFTR co-precipitate and CK2 co-localized with wtCFTR (but not ΔF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and ΔF508CFTR expressing oocytes, only ΔF508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the ΔF508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not ΔF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by ΔF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR.

Original languageEnglish
Pages (from-to)347-360
Number of pages14
JournalCellular Physiology and Biochemistry
Volume24
Issue number5-6
DOIs
Publication statusPublished - Jan 1 2009

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Keywords

  • ATP-binding cassette transporter
  • CFTR
  • Channel regulation
  • Chloride ion channel
  • Cystic fibrosis
  • Protein kinase CK2

ASJC Scopus subject areas

  • Physiology

Cite this

Treharne, K. J., Xu, Z., Chen, J. H., Best, O. G., Cassidy, D. M., Gruenert, D. C., Hegyi, P., Gray, M. A., Sheppard, D. N., Kunzelmann, K., & Mehta, A. (2009). Inhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant Δf508-CFTR. Cellular Physiology and Biochemistry, 24(5-6), 347-360. https://doi.org/10.1159/000257427