... Cardiac Gap Junctions Physiology, Regulation, Pathophysiology and Pharmacology

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1 ... Cardiac Gap Junctions Physiology, Regulation, Pathophysiology and Pharmacology S. Dhein, Cologne 23 figures and 3 tables, 1998

2 StefanDhein InstituteofPharmacology UniversityofCologne (Germany) All rights reserved. No part of this publication may be translated into other languages, reproduced or utilizedin anyform orbyany means,electronicor mechanical,including photocopying,recording,microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. ÓCopyright 1998 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN IV

3 Dedicated to Aida V

4 Contents Foreword... IX Preface... XI 1 Introduction: Cellular Coupling, Cardiac Activation Patterns and Arrhythmia Structure and Diversity of Gap Junction Channels Distribution of Gap Junctions in the Heart Function and Physiology of Gap Junction Channels Regulation of Gap Junction Expression, Synthesis and Assembly Gap Junctions in Cardiac Disease Pharmacological Interventions at Gap Junctions Methods for Investigation of Gap Junctions References Appendix List of Suppliers of Specialized Items Subject Index VII

5 Foreword When I started as a novice in the field of cardiac electrophysiology, the dogma was that gap junctions are specialized membrane structures present in the cardiac and smooth muscle of vertebrates where they serve to propagate the action potential from cell to cell. Purkinje fibers and muscular trabeculae were the preferred cardiac preparations. These multicellular preparations were suitable to perform cable analyses and diffusion studies. At that time, my mentor, Silvio Weidmann, had already accomplished his elegant functional studies. The subsequent progress in the field was prompted largely by the development of novel experimental approaches. On the one hand, the introduction of the patch-clamp method and the use of cell pairs led to a detailed description of the intercellular current flow. As a result, we nowadays have extensive knowledge about the conductive and kinetic properties of gap junctions and gap junction channels. On the other hand, immunohistochemistry and molecular biology made one aware of the diversity of gap junction proteins and their distribution in tissues of the cardiovascular system. This reductionistic approach led to the accumulation of an enormous amount of functional and structural details. The combination of electrophysiology and molecular biology will culminate eventually in the elucidation of the structure-function relationship of a single channel. However, scientists soon should explore the reverse path and try to integrate the collected data in the context of an intact heart. In this way, the knowledge gathered may provide a basis for new strategies against cardiovascular diseases. Hopefully, this monograph will contribute to this process. Robert Weingart Berne, June 23, 1997 IX

6 Preface Cells live together and die singly Engelmann wrote at the end of the past century. With this simple sentence he summarized the key feature provided by cell coupling via gap junction channels: these channels provide exchange of small molecules and electrical coupling in the intact heart, but in the course of ischemia, for example, they close, the cell gets isolated and is no longer activated by the surrounding tissue. This may help the cell to survive, or the cell dies but without influencing the adjacent cells. In the chronic phase of cardiac disease the distribution of various gap junction isoforms can change, thereby altering the tissue s biophysics. This behavior opens new perspectives for arrhythmia research, for drug research and for research directed toward ischemia, cardiac protection and cardiac pathophysiology. The following book is written to give an insight into a relatively new field of cardiovascular research to basic researchers, cardiologists, physiologists and pharmacologists who wish to obtain information on cellular coupling in the heart or who wish to enter this new field of research. Therefore, the first chapter gives an introduction to the various aspects of activation propagation and coupling in the heart. This is followed by two chapters which review our present knowledge on the structural aspects of gap junction channels including amino acid sequences and species variability as known so far. Thereafter, the physiology of gap junction channels and the regulation of expression is described in the subsequent two chapters. Since it is known today that gap junction distribution can change in the course of cardiac disease, these changes and their implications are described in the sixth chapter. The seventh chapter then gives insight into pharmacological approaches to the modulation of gap junction channel conductivity and outlines possible new therapeutic strategies. The final chapter is especially written for people who are interested in entering this fascinating field of cardiovascular research and describes practical approaches to gap junction research. The concept of double-cell voltage clamp, immunohistochemistry, isolation procedures for gap junctions and dye-coupling assays are described with practical protocols. At the end of the book a list of suppliers of specialized items, such as certain amplifiers, antibodies etc., is given. Stefan Dhein Cologne, April 1997 XI

Cardiac cell-cell Communication Part 1 Alonso P. Moreno D.Sc. CVRTI, Cardiology

Bioengineering 6003 Cellular Electrophysiology and Biophysics Cardiac cell-cell Communication Part 1 Alonso P. Moreno D.Sc. CVRTI, Cardiology moreno@cvrti.utah.edu November 2010 poster Physiological Relevance