Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant ΔF508-CFTRTreharne K.J. · Xu Z.1 · Chen J.-H.1 · Best O.G.1 · Cassidy D.M.1 · Gruenert D.C.2 · Hegyi P.3 · Gray M.A.4 · Sheppard D.N.1 · Kunzelmann K.5,* · Mehta A.*
Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, University of Dundee, Ninewells Hospital, Dundee,1Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol2California Pacific Medical Centre Research Institute, San Francisco; Department of Laboratory Medicine, University of California, San Francisco, Department of Medicine, University of Vermont School of Medicine, Burlington,3First Department of Medicine, University of Szeged, Szeged,4Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne,5Institut für Physiologie, Universität Regensburg, Regensburg,*KK and AM are co-last authors
Prof. Dr. Karl Kunzelmann
Institut für Physiologie, Universität Regensburg
Universitaetstrasse 31, 93053 Regensburg (Germany)
Tel. +499419434302, Fax: +499419434315
Do you have an account?
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.
© 2009 S. Karger AG, Basel
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.