Defects of Secretion in Cystic Fibrosis

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University of New York at Buffalo

IRUN R. COHEN, The Weizmann Institute of Science

DAVID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, A. S. Kline Institute for Psychiatric Research

RODOLFO PAOLETTI, University of Milan

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Volume 558 DEFECTS OF SECRETION IN CYSTIC FIBROSIS

Edited by Carsten Schultz

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Defects of Secretion in Cystic Fibrosis

Edited by

Carsten Schultz European Molecular Biology Laboratory Heidelberg, Germany

Spri ringer

Library of Congress Cataloging-in-Publication Data

Defects of secretion in cystic fibrosis/edited by Carsten Schultz. p. ; cm. — (Advances in experimental medicine and biology; v. 558)

Includes bibliographical references and index. ISBN 0-387-23076-9 (alk. paper)

1. Cystic fibrosis—Pathophysiology. 2. Cystic fibrosis—Molecular aspects. I. Schultz, Carsten. II. Series.

[DNLM: 1. Cystic Fibrosis—physiopathology—Congresses. 2. Cystic Fibrosis—therapy—Congresses. 3. Cystic Fibrosis Transmembrane Conductance Regulator—Congresses. 4. Pancreas—secretion—Congresses. WI 820 D313 2005] RC858.C95D44 2005 616.372—dc22

2004063217

ISBN: 0-387-23076-9 elSBN: 0-387-23250-8

©2005 Springer Science+Business Media, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science-!-Business Media, Inc., 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

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Acknowledgments

I would like to thank Sylke Helbing and Bettina Schafer for editorial help and Nicole Heath for critically reading through part of the manuscripts. I also would like to acknowledge all speakers and participants of the 'Defects of Secretion' symposium held in Heidelberg in November 2003. Your contributions and lively discussions made the compilation of this book worth while.

Contributing Authors

Gabriele Adam Universitat Regensburg, Germany

Susan J. Anderson University of Alabama at Birmingham, AL, USA

Tanja Bachhuber Universitat Regensburg, Germany

Dale J. Benos University of Alabama at Birmingham, AL, USA

Christoph Bohmer Eberhard-Karls-Universitat Tubingen, Germany

Horst Fischer Children's Hospital Oakland Research Institute, Oakland, CA, USA

Catherine M. Fuller University of Alabama at Birmingham, AL, USA

Sherif Gabriel University of North Carolina, Chapel Hill, NC, USA

Erich Gulbins Eberhard-Karls-Universitat Tubingen, Germany

1 CONTRIBUTING AUTHORS

Gunnar C. Hansson Goteborg University, Gothenburg, Sweden

Jean-Daniel Horisberger University Lausanne, Switzerland.

Beate lUek Children's Hospital Oakland Research Institute, Oakland, CA, USA

Malin E. V. Johansson Goteborg University, Gothenburg, Sweden

Reinhard Kandolf Eberhard-Karls-Universitat Tubingen, Germany

RolfK.-H.Kinne Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany

Helmut Kipp Max-Planck-Institut fiir molekulare Physiologie, Dortmund, Germany

Karin Klingel Eberhard-Karls-Universitat Tubingen, Germany

Gergely Kovacs University of Alabama at Birmingham, AL, USA

Karl Kunzelmann Universitat Regensburg, Germany

Florian Lang Eberhard-Karls-Universitat Tubingen, Germany

Albrecht Lepple-Wienhues Eberhard-Karls-Universitat Tubingen, Germany

Martin E. Lidell Goteborg University, Gothenburg, Sweden

Marcus Mall The University of North Carolina, Chapel Hill, NC, USA

CONTRIBUTING AUTHORS

Mark Moody Inologic Inc., Seattle, WA, USA

Bettina Murle Universitat Regensburg, Germany

Paul M. Quinton UCSD School of Medicine, La JoUa, CA, USA

Monica Palmada Eberhard-Karls-Universitat Tubingen, Germany

Caria M. Pedrosa Ribeiro The University of North Carolina, Chapel Hill, NC, USA

Andres Ponce UCSD School of Medicine, La JoUa, CA, USA

Marsh M, Reddy UCSD School of Medicine, La Jolla, CA, USA

Philippe Roussel Universite de Lille 2, Lille, France

Rainer Schreiber Universitat Regensburg, Germany

Carsten Schultz European Molecular Biology Laboratory, Heidelberg, Germany

Steve B. Shears N.LE.H.S./N.LH./D.H.S.S., Research Triangle Park, NC, USA

Udicko Szabo Eberhard-Karls-Universitat Tubingen, Germany

Alexis Traynor-Kaplan hiologic Lie, Seattle, WA, USA

Frank Thevenot, Universitat Witten/Herdecke, Witten, Germany.

CONTRIBUTING AUTHORS

Thilo Voelcker Universitat Regensburg, Germany.

Sabine Wallisch Eberhard-Karls-Universitat Tubingen, Germany

Ling Yang N.LE.H.S./N.LH./D.H.S.S., Research Triangle Park, NC, USA.

Preface

Cystic fibrosis (CF) is the most abundant homocygote inherited disease in the western world. There are about 60,000 patients worldwide. Despite a stable number of new incidents the total number is increasing due the fact that the average lifespan of CF patients has increased from about 8 years in the 1960's to currently over 30 years. Genetic analysis has certainly added patients with mild manifestations who were previously not recognized as CF patients. Overall, however, the increase in life expectancy is mainly due to improved treatment in hospitals and increased knowledge and expertise of physicians around the world. This process has been largely fostered by implementation of CF centers in the US and Europe, where the concentration of required expertise can be more efficiently provided by a team of physicians than in a doctor's practice. The focus, however, needs to expand from the predominantly pediatric level to the treatment of adult patients, a tremendous task for clinics and caretakers. In comparison, the achievements of basic research appear to be very moderate. Laboratories have yet to produce a drug that reverses the basic defect, although several drug candidates that promise increases in chloride secretion and a reduction of the pathologically high sodium uptake of airway epithelia are in clinical trials.

In a meeting, held at the European Molecular Biology Laboratory (EMBL) late in 2003, an international group of scientists gathered to discuss current developments in basic research and novel ways to treat CF. The present volume contains contributions from many of the meeting's speakers and the subjects are wide-ranging encompassing mucus secretion, intracellular epithelial signaling, and the nature and regulation of epithelial ion channels, as well as some of the most recent ideas to prepare CF drug candidates based on intracellular signaling molecules.

Contents

1. Outside Neurons/Inside Epithelia: Novel Activation of CFTR CI' and HCOs" Conductances 1

Marsh M. Reddy, Andres Ponce, and Paul M. Quinton

2. Role of CFTR and Other Ion Channels in Cystic Fibrosis 23 Karl Kunzelmann, Tanja Bachhuber, Gabriele Adam, Thilo Voelcker,

Bettina Mtirle, Marcus Mall, and Rainer Schreiber

3. Ion Channels in the Apical Membrane: Role of Electrical Coupling on Transepithelial Transport 43

Jean-Daniel Horisberger

4. Ion Channels in Secretory Granules of the Pancreas: Molecular Identification and Their Role in Regulated Secretion 53

Frank Thevenod

5. Epithelial Transport and Intracellular Trafficking: Physiology and Pathophysiology 67

Helmut Kipp and Rolf K. H. Kinne

6. Kinases, Cell Volume, and the Regulation of Chloride Channels 73 Florian Lang, Albrecht Lepple-Wienhues, Ildicko Szabo,

Erich Gulbins, Monica Palmada, Sabine Wallisch, Christoph Bohmer, Karin Klingel, and Reinhard Kandolf

7. The CLCAs: Proteins with Ion Channel, Cell Adhesion and Tumor Suppressor Functions 83

Catherine M. Fuller, Gergely Kovacs, Susan J. Anderson, and Dale J. Benos

8. Is Intervention in Inositol Phosphate Signaling a Useful Therapeutic Option for Cystic Fibrosis? 103

Stephen B. Shears, Ling Yang, Sherif Gabriel, and Carla M. Pedrosa Ribeiro

xiv CONTENTS

9. An Inositol Phosphate Analog, rNO-4995, Normalizes Electrophysiology inCF Airway Epithelia 115

Alexis Traynor-Kaplan, Mark Moody, and Carsten Schultz

10. Vitamin C and Flavonoids Potentiate CFTR CI Transport in Human Airway Epithelia 129

Horst Fischer and Beate lUek

11. Airway Glycoconjugates Secreted in Cystic Fibrosis and Severe Chronic Airway Inflammation Relationship with Pseudomonas aeruginosa .... 145

Philippe Roussel

12. Biosynthesis and Secretion of Mucins, Especially the MUC2 Mucin, in Relation to Cystic Fibrosis 169

Gunnar C. Hansson, Malin E. V. Johansson, and Martin E. Lidell

Index 179

Chapter 1

OUTSIDE NEURONS/INSIDE EPITHELIA: NOVEL ACTIVATION OF CFTR CL AND HCO3 CONDUCTANCES

Marsh M. Reddy\ Andres Ponce\ and Paul M. Quinton ' ^Department of Pediatrics, UCSD School of Medicine, La Jolla, California 92093-0831; ^Division of Biomedical Sciences, University of California Riverside, Riverside, CA 92021, USA. Phone 001-619-543-2884, fax 001-619-543-568, e-mail: pquinton@ucsd.edu

1. INTRODUCTION

Cystic Fibrosis (CF) is a disease of abnormal electrolyte transport caused by defects in an anion selective channel, "CFTR". The disease is characterized by poor salt absorption in exocrine ducts, poor cAMP dependent bicarbonate and fluid secretion by pancreas, intestine, and other exocrine epithelia. CF causes an early onset of refractory airway infections that usually eventually result in respiratory failure. The link between the electrolyte transport defect and chronic lung infection remains poorly understood.

The CFTR channel is located specifically in the apical membrane of certain secretory cells and in both luminal and basilateral membranes of absorptive cells.^ The channel protein is a large complicated structure composed of 1480 amino acids forming 12 transmembrane domains, 2 cytosolic nucleotide binding domains and a cytosolic putatively referred to as regulatory domain because of the numerous consensus phosphorylation sites present in it. The mature protein when expressed in the plasma membrane also exhibits two glycosylated sites on the extracellular surface.

Since the early work of Sato,^ cAMP activation of protein kinase A mediated phosphorylation has been an accepted and apparently become a universal method for stimulating the CFTR dependent CI" conductance. In