Table Of ContentAN ESSENTIAL P A D n i A P
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INTRODUCTION TO
ELECTROPHYSIOLOGY
Ken MacLeod
Imperial College Press
AN ESSENTIAL IP HA nQU11I1 HA Pl
INTRODUCTION TO
ELECTROPHYSIOLQGY
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A
AN ESSENTIAL I
INTRODUCTION TO
rnTnnnii V S l O E Y
Ken MacLeod
Imperial College, London, UK
Imperial College Press
Published by
Imperial College Press
57 Shelton Street
Covent Garden
London WC2H 9HE
Distributed by
World Scientific Publishing Co. Pte. Ltd.
5 Toh Tuck Link, Singapore 596224
USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601
UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
AN ESSENTIAL INTRODUCTION TO CARDIAC ELECTROPHYSIOLOGY
Copyright © 2014 by Imperial College Press
All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means,
electronic or mechanical, including photocopying, recording or any information storage and retrieval
system now known or to be invented, without written permission from the Publisher.
Forphotocopying of material in this volume, please pay a copying fee through the Copyright Clearance
Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy
is not required from the publisher.
ISBN 978-1-908977-34-2
ISBN 978-1-908977-35-9 (pbk)
Printed in Singapore
To my father, Alasdair.
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Contents
Preface.....................................................................................................xiii
Chapter I Introduction................................................................................I
I. I Early references to the heart and its function.................................I
1.2 Early references to electrical properties.......................................3
1.3 The electrocardiograph..................................................................4
1.4 Cellular electrophysiology............................................................7
1.5 Heart anatomy and location..........................................................7
1.6 How this book is organized.........................................................13
1.7 Bibliography................................................................................15
Chapter 2 The Resting Membrane Potential............................................17
2.1 Chapter objectives.......................................................................17
2.2 How is the resting membrane potential generated?.....................17
2.2.1 What is the Nernst equation?.............................................20
2.2.2 How does changing the potential difference affect
ion flow?............................................................................22
2.3 K+ ion and the membrane potential..............................................22
2.3.1 What are the equilibrium potentials for other ions in the
heart?..................................................................................24
2.3.2 How do other ions contribute to the resting potential?....24
2.3.3 What is the influence of the Na+/K+ pump on the
membrane potential?..........................................................29
2.3.4 What is the effect of changing extracellular [K+] on the
membrane potential?..........................................................32
2.4 Summary.......................................................................................33
2.5 Questions........................................................................................33
2.6 Bibliography..................................................................................34
Chapter 3 Measuring Membrane Currents...............................................35
3.1 Chapter objectives.......................................................................35
3.2 Key electrical concepts: voltage, current, conductance and
capacitance...................................................................................36
vii
An Essential Introduction to Cardiac Electrophysiology
3.2.1 Voltage...............................................................................36
3.2.2 Current...............................................................................36
3.2.3 Conductance.......................................................................37
3.2.4 Capacitance........................................................................38
3.3 What is voltage clamp?................................................................40
3.4 Hodgkin and Huxley experiments................................................43
3.4.1 Separating the early and late currents...............................46
3.4.2 Na+ and K+ channels conduct in a voltage- and time-
dependent manner..............................................................47
3.4.3 Activation and inactivation of channels............................48
3.5 Conclusions..................................................................................53
3.6 Summary......................................................................................56
3.7 Questions......................................................................................58
3.8 Bibliography.................................................................................59
3.8.1 Books and reviews.............................................................59
3.8.2 Originalpapers...................................................................60
Chapter 4 Channel Structure and Function.............................................61
4.1 Chapter objectives........................................................................61
4.2 Ions flow through separate channels............................................61
4.3 Channels can be activated (or “gated”) in various ways.............62
4.4 Channels are specialized to allow the transport of specific ionic
species...........................................................................................63
4.5 Channels can discriminate between ions......................................63
4.6 Channels can pass large ionic currents.........................................63
4.7 Some channels can sense voltage.................................................65
4.8 Biophysical techniques - the patch clamp..................................65
4.8.1 Ensemble currents..............................................................66
4.8.2 Other patch clamp configurations.....................................70
4.9 Molecular techniques - working with frogsa nd fruit flies..........72
4.9.1 Frogs..................................................................................72
4.9.2 Fruitflies............................................................................73
4.10 Microscopy, electron diffraction and cryo-electron microscopy 75
4.11 More understanding of channel structure and function...............76
4.12 Channel subunits..........................................................................77
4.13 Channel structure.........................................................................78
4.13.1 Protein structure - a recap................................................78
4.13.2 K+ channel structure.........................................................80
Contents ix
4.14 The structural basis of ion channel function...............................84
4.14.1 Sensing the voltage across the cell membrane................84
4.14.2 Moving ions into the channel...........................................85
4.14.3 Discriminating between ions............................................88
4.15 Na+ channels.................................................................................94
4.16 Channel inactivation....................................................................96
4.17 Other ways of altering channel function.....................................99
4.18 Questions......................................................................................99
4.19 Bibliography................................................................................100
4.19.1 Books and reviews.........................................................100
4.19.2 Originalpapers...............................................................100
Chapter 5 Active Transporters..............................................................105
5.1 Chapter objectives......................................................................105
5.2 What do active transporters do?.................................................105
5.3 ATPases or pumps.....................................................................106
5.3.1 Na+/K+-ATPase................................................................107
5.3.2 Na4VK+ pump isoforms.....................................................Ill
5.3.3 Na+/K+ pump current and intracellular [Na+]..................112
5.4 Ion exchangers............................................................................114
5.4.1 Na+/Ca2+ exchanger..........................................................114
5.4.2 Na+/H+exchanger.............................................................120
5.5 Interaction of ion transporters in the heart.................................122
5.5.1 The effect of alterations to intracellular [Na+] on
contractile force...............................................................122
5.5.2 The effect of alterations to intracellular pH on contractile
force..................................................................................124
5.5.3 Interactions between H+ and Ca2+....................................124
5.6 Summary.....................................................................................126
5.7 Questions.....................................................................................127
5.8 Bibliography................................................................................128
5.8.1 Reviews.............................................................................128
5.8.2 Originalpapers.................................................................129
Chapter 6 Currents Flowing During the Early Part of the Ventricular
Action Potential....................................................................131
6.1 Chapter objectives......................................................................131
