Treharne, Kate J. and Xu, Zhe and Chen, Jeng-Haur and Best, O. Giles and Cassidy, Diane M. and Gruenert, Dieter C. and Hegyi, Peter and Gray, Michael A. and Sheppard, David N. and Kunzelmann, Karl and Mehta, Anil (2009) Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant Delta F508-CFTR. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 24 (5-6). pp. 347-360. ISSN 1015-8987, 1421-9778
Full text not available from this repository. (Request a copy)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
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSMEMBRANE-CONDUCTANCE-REGULATOR; PANCREATIC-DUCT CELLS; BRONCHIAL EPITHELIAL-CELLS; POLYAMINE METABOLISM; CHAPERONE CALNEXIN; CHLORIDE CHANNEL; INTRACELLULAR PH; FLUID SECRETION; PLASMA-MEMBRANE; HCO3-SECRETION; ATP-binding cassette transporter; CFTR; Chloride ion channel; Channel regulation; Cystic fibrosis; Protein kinase CK2 |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Oct 2020 09:02 |
| Last Modified: | 09 Oct 2020 09:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/29660 |
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