sodium channels and neuronal hyperexcitability

SODIUM CHANNELS AND NEURONAL HYPEREXCITABILITY Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 The Novartis Foundation is an international scienti¢c and educational charity (UK Registered Charity No. 313574). Known until September 1997 as the Ciba Foundation, it was established in 1947 by the CIBA company of Basle, which merged with Sandoz in 1996, to form Novartis. The Foundation operates independently in London under English trust law. It was formally opened on 22 June 1949. The Foundation promotes the study and general knowledge of science and in particular encourages international co-operation in scienti¢c research. To this end, it organizes internationally acclaimed meetings (typically eight symposia and allied open meetings and 15^20 discussion meetings each year) and publishes eight books per year featuring the presented papers and discussions from the symposia. Although primarily an operational rather than a grant-making foundation, it awards bursaries to young scientists to attend the symposia and afterwards work with one of the other participants. The Foundation’s headquarters at 41 Portland Place, London W1N 4BN, provide library facilities, open to graduates in science and allied disciplines. Media relations are fostered by regular press conferences and by articles prepared by the Foundation’s Science Writer in Residence. The Foundation o¡ers accommodation and meeting facilities to visiting scientists and their societies. Information on all Foundation activities can be found at http://www.novartisfound.org.uk Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 20 02 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Novartis Foundation Symposium 241 SODIUM CHANNELS AND NEURONAL HYPEREXCITABILITY 2002 JOHN WILEY & SONS, LTD Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Copyright & Novartis Foundation 2002 Published in 2002 byJohnWiley & Sons Ltd, Ba⁄ns Lane, Chichester, West Sussex PO19 1UD, England National 01243 779777 International (+44) 1243 779777 e-mail (for orders and customer service enquiries): c s-books@wiley.co.uk Visit our Home Page on http://www.wiley.co.uk or http://www.wiley.com Al l Rights Reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recordi ng, scann ing or otherwise, except under the terms of the C opyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London,W1P 9HE, UK, without the permission in writing of the publisher. Other Wiley Editorial O⁄ces JohnWiley & Sons, Inc., 605 Th ird Avenue, NewYork, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Papp elallee 3, D-69469 Weinheim, Germany Jacaranda Wiley Ltd, 33 Park Road, Milton , Queensland 4064, Australia JohnWiley & Sons (Asia) Pte Ltd, 2 C lementi Loop #02-01, Jin Xing Distripark, Singapore 129809 JohnWiley & Sons (Canada) Ltd, 22 Worcester Road, Rexdale, Ontario M9W 1L1, Canada Novartis Foundation Symposium 241 viii+244 pages, 42 ¢gures, 5 tables Library of Congress Cataloging-in-Publication Data Sodium channels and neuronal hyperexcitability / [editors], Gregory Bock, Jamie A. Goode. p. cm. ^ (Novartis Foundation symposium ; 241) (Ciba Foundation symposium) Includes bibliographical re ferences and index. ISBN 0-471-48530-6 (alk. paper) 1. Sodium channels ^Congresses. 2. Molecular neurobiology^Congresses. 3. Nervous system^Diseases ^Molecular aspects ^Congresses. 4. Neurons ^Congresses. I. Bock, Gregory. II. Goode, Jamie. III. Series. IV. Series: Ciba Foundation symposium QP356.2.S65 2001 612.8’042^dc21 2001046625 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN0471485306 Ty p e s e t i n 10 1 Ù 2 on 12 1 Ù 2 pt Garamond by DobbieTypesetting Limited,Tavistock, Devon. Printed and bound in Great Britain by Biddles Ltd, Guildford and King’s Lynn. This bo ok is printed on acid-free paper responsibly manufactured from sustainable forestry, in which at least two trees are planted for each one used for paper production. Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 20 02 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Contents Symposium on Sodiumchannels and neuronal hyperexcitability, held atthe Novartis Foundation, London,14^16 November 2000 Editors: Gregory Bock (Organizer) a nd Jamie A. Goode Thissymposium is based on aproposalmade by JohnWood and StephenWaxman in conjunction with theYale^University College London Collaboration Stephen G.Waxman Chair’s introduction: Sodium channels and neuronal dysfunction ö emerging conc epts, converging themes 1 Richard D. Keynes Studies of multimodal gating of the sodium channel 5 Discussion 14 Richard Horn Molecular basis for fu nction in sodium cha nnels 21 Discussion 26 Stephen G.Waxman,Theodore R. Cummins, Joel A. Black and Sulayman Dib-Hajj Diverse functions and dynamic expression of neuronal sodium channels 34 Discussion 51 Wayne E. Crill, Peter C. Schwindt andJohn C. Oakley Enhanced transmission of glutamate current £owing from the dend rite to the soma in rat neocortical layer 5 neurons 61 Discussion 68 Mi riam H. Meisler, Jennifer A. Kearney, Leslie K. Sprunger, BryanT. MacDonald, David A. Buchner and Andrew Escayg Mutations of voltage-gated sodium channels in movement disorders and epilepsy 72 Discussion 82 Louis P tacek Channelopathies: episodic disorder s of the nervous system 87 Discussion 104 Je ¡rey L. Noebels Sodium channel gene expression and epilepsy 109 Discussion 120 v Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Lori L. Isom b subunits: players in neuronal hyperexcitability? 124 Discussion 138 Stuart Bevan and Ni na Storey Modulation of sodium channels in primary a¡erent neurons 144 Discussion 153 John N.Wood, Armen N. Akopia n, Mark Baker,Yanning Ding, Fleur Geoghegan, Mohammed Nassar, Misbah Malik-Hall, Kenji Okuse, Louisa Poon, Samantha Ravenall, Madhu Suku maran and Veronika Souslova Sodium channels in primary s ensory neurons: relationship to pain states 159 Discussion 168 Michael M. Segal Sodium channels and epilepsy ele ctrophysiology 173 Discussion 180 Gar y R. Strichartz, Zhongren Zhou, Catherine Sinnott and Alla Khodorova Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in n europathic pain 189 Discussion 202 William A. Catterall Molecular mechanisms of gating and drug blo ck of sodium channels 206 Discussion 218 Final general discussion 226 Index of contributors 233 Subject index 235 vi CONTENTS Participants Mark D. Baker Dep artment of Biology, University C ol lege London, Medawar Building, Gower Stre et, LondonWC1E 6BT, UK Bruce Bean Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA Stuar t Bevan Novartis Institute for Medical Science, University College London, Gower Street, LondonWC1E 6BT, UK Hugh Bostock Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, LondonWC1N 3BG, UK William A. Catterall Department of Pharmacology, F-427 Health Sciences Center, University o f Washington, Se attle,WA 98195-7280, USA Way n e C r i l l Department of Physiology and Biophysics, University of Washington, 1959 NE Paci¢c Street, HSB Room G424, Box 357290, Seattle, WA 9 8195 -72 9 0, USA Ted R. Cummins Department of Neurology,Yale University, New Haven, CT 06520, USA Michael S. Gold Oral and Craniofacial Biological Sc iences, University of Maryland Dental School, 666 W. Baltimore Street, Baltimore, MD 21201, US A Alan L. Goldin Department of Microbiology & Molecular Genetics, University of California at Irvine, Irvine, CA 92697-4025, USA Richard Horn Department of Physiology, Institute of Hyperexcitability, Je¡erson Medical College, 1020 Locust Street, Philadelphia, PA19107, USA vii Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Lori L. Isom Department of Pharmacology,The University of Michigan Medical School, 1301MSRB I II,1150 W. Medical C enter Drive, Ann Arbor, MI 48109- 0 632, USA Richard Keynes Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK Miriam Meisler Department of Human Genetics, University of Michiga n Medical School, Ann Arbor, MI 48109-0618, USA Je¡rey L. Noebels Department of Neurology, Baylor College of Medicine, On e Baylor Plaza, Houston,TX 77030, USA Louis Ptacek Howard Hughes Medical Institute, University of Utah School of Medicine, Room 4425, Salt Lake City, UT 84112-5331, USA Indira M. Raman Department of Neurobiology and Physiology, Northwestern University, 2153 North Campus Drive, Evanston, Illinois 60208-3520, USA Michael Segal Harvard Medical School and Brigham & Women’s Hospital, Longwood Medical Research Center, 221Longwood Ave, Boston MA 02115, USA Nelson Spruston Department o f Neurobiology and Physiology, Northwestern University, 2153 N. Campus Drive, Evanston, IL 6 0208 -3520, USA Gary R. Strichartz Pain Research Center, Harvard Medical School, Anaesthesia Research Laboratories, Medical Research Buildi ng 611, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA Stephen Waxman (Chair) Department of Neurology,Yale Medical School, 333 Cedar Street, LCI-707, New Haven, CT 06510, USA JohnWood Department of Biology, University College London, Medawar Building, Gower Stre et, LondonWC1E 6BT, UK viii PARTICIPANTS Subject index A accessory subunits 161^162 see also b subunits acetazolamide (Diamox) 91, 93, 231 acetylcholine (ACh) 95, 96 see also nicotinic acetylcholine receptor activation 22 b scorpion toxin action 209, 210 coupling to inactivation 211^213 gate immobilization 24^25, 27 hyperpolarized dependence 38 molecular basis 31, 208^209, 210 Ad ¢bres 161 adenosine 149, 178 adenovirus vectors 165 allodynia, mechanical 191, 192, 204 a scorpion toxins binding sites 207 local anaesthetic actions and 192^194, 204 mechanism of action 213, 214, 222^224 a subunits 2, 89, 206^207 interaction site with b subunits 31^32, 126^128 modulation by b subunits 124^125 nomenclature 3 phosphorylation 145 in sensory neurons 160 D-2-amino-5-phosphonopentoic acid see APV amygdala in epileptogenesis 114 SCN5A localization 112, 113 analgesics, future prospects 161^162 Andersen’s syndrome 107 ankyrin 129^130, 134, 142 ankyrin G 133, 135 antagonists, Na + channel anticonvulsant activity 176^177 molecular mechanisms 213^216, 218^222 in neuropathic pain 189^205 novel 216, 219 anti-arrhythmic drugs 186, 215, 223 anticonvulsants binding site 183^184, 215 mechanisms of action 176^178, 184^185, 186, 223 antisense Na v 1.8 (SNS, PN3) 170^171, 190 APV 62, 63, 64, 175, 185^186 astrocytes 52, 123, 134, 135, 142 ataxia episodic see episodic ataxia mutant mouse models 45^48, 76^78, 94^95 progressive cerebellar (SCA6) 94, 99 axotomized neurons 42^45, 46, 51^52, 53, 55^59 B BIII 890 CL (novel Na + channel blocker) 216, 219 BAC clones 86 ba¢lomycin A 152 bed nucleus of stria terminalis 112 benzophenone-4-carboxamidocysteine methanethiosulfonate (BPMTS) 23, 24, 26^27, 28, 29, 30^31 b scorpion toxins 207, 208^209, 210, 213, 222^224 b subunits 2, 89, 124^143, 161, 206 a subunit interaction site 31^32, 126^128 in cardiac myocytes 130^131 evolution 229 function as CAMs 128^130, 208 in heterologous expression systems 125 homophilic interactions 129^130 in human disease 131^133 modulation of channel gating 124^125 mutations 107 phosphorylation 139^140, 141^142 structural homology to CAMs 126 structure 207^208 see also speci¢c subtypes 235 Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 b1 subunits 124^125, 126, 161 a scorpion toxin and 222^223 in cardiac physiology 131 function as CAMs 129^130 in heterologous expression systems 125 Ig loop region in a subunit interactions 126^128 mutations 110^111 in neuropathic pain 133 NGF e¡ects 162 structure 207^208 b1A subunits 125, 126, 161 b2 subunits 124^125, 126, 161 in cardiac physiology 131 function as CAMs 128, 129^130 knockout mice 142 in neuropathic pain 133 structure 207^208 b3 subunit 125, 126, 161 Bezanilla’s crevices 9^11, 23, 32^33 bicarbonate ions 231 biolistic gene gun 164 blockers, Na + channel see antagonists, Na + channel brefeldin 157 8-bromo-cAMP 146^147, 149 Brugada syndrome 123, 132^133 a-bungarotoxin 96 bursting frog skeletal muscle channels 11, 13, 16^17 neuronal 17, 178, 204 C C-¢bres 53, 59, 161 CA1 neurons 71, 73^74 Ca 2+ intracellular, DRG neurons 156, 157 spikes 69, 70^71, 88 zero 185^186 Ca 2+ channel blockers 69 Ca 2+ channels 229 b subunits 125 L-type 88, 213 mutations 92, 94^95, 99 neocortical layer 5 neurons 68^69 structure 22, 88^89 CACNA1A mutations 94, 100^101 cadmium (Cd 2+ ) 36, 37, 38, 71 Caenorhabditis elegans 229 CAG repeat expansions 94 calcineurin 145 calcium see Ca 2+ CAMs see cell adhesion molecules carbamazepine 186 carbonic anhydrase inhibitors 91, 93, 230, 231 cardiac glycosides 122 cardiac myocytes b subunits 130^131 Na + channel targeting and clustering 135 cartwheel cells, dorsal cochlear nucleus 76 cell adhesion molecules (CAMs) b subunit function 128^130, 208 L1 family 129, 130, 142 nodes of Ranvier 133^135, 138 structural homology of b subunits 126 cell migration, b subunits and 128^129 cellular aggregation, b subunits and 129^130 channelopathies acquired 2 inherited see inherited channelopathies chloroquine 152 choreoathetosis, paroxysmal dystonic 101 chronic constriction injury 133, 163 Cl 7 channels 87^88 mutations 92^93, 99 structure 89 CLCN1 mutations 92^93 CNQX 175, 185^186 Cole^Moore e¡ect 32 m conotoxin 223 contactin 126, 134, 135, 138 convulsions see seizures cooperativity, S4 segment domains 15^16, 29 cornea 160^161 Cre/lox-P system 164^165 crevices, Bezanilla’s 9^11, 23, 32^33 cultures, microisland 174^178 cyclic AMP (cAMP) 145^147, 149, 162 cycloheximide 158 cysteine accessibility scanning 8^9, 22^23, 31^32, 209, 211 cytoplasmic loop domains 229 cytoskeletal interactions 130, 133^135, 139, 228 236 SUBJECT INDEX [...]... 90 window currents 38^39, 226 X Xenopus oocytes a and b subunit coexpression 125, 126^127, 140 b subunit function as CAMs 128, 129 mutant SCN2A expressing 73^74 Sodium Channels and Neuronal Hyperexcitability Novartis 241 Copyright & 2002 John Wiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Chair’s introduction: sodium channels and neuronal dysfunction ö emerging concepts, converging... welcome everyone and thank you for coming I know we will have an interesting week Reference Goldin AL, Barchi RL, Caldwell JH et al 2000 Nomenclature of voltage-gated sodium channels Neuron 28:365^368 Sodium Channels and Neuronal Hyperexcitability Novartis 241 Copyright & 2002 John Wiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Studies of multimodal gating of the sodium channel Richard... channels that contribute to neuronal function and dysfunction Theme number two is a very rich biology Di¡erent channels may subserve di¡erent roles in di¡erent cell types, and possibly under di¡erent conditions We are beginning to understand the complex network of factors and molecules that control or modulate channel expression and function We are also beginning to understand dynamic aspects of channel... are learning more and more, by the month, about the role of Na+ channels in electrogenesis, and about the many ways in which the various channels contribute to it We also now know that Na+ channels are key players in some neurological diseases, including disorders that re£ect neuronal hyperexcitability This meeting will focus on an emerging concept, that a multiplicity of molecularly and physiologically... potassium channels J Gen Physiol, in press (Soc Gen Physiol Symp 54, Massachusetts, 2000) Catterall WA 1986 Voltage-dependent gating of sodium channels: correlating structure and function Trends Neurosci 9:7^10 Chandler WK, Meves H 1970 Evidence for two types of sodium conductance in axons perfused with sodium £uoride solution J Physiol 211:653^678 Correa AM, Bezanilla F 1994 Gating of the squid sodium. .. and physiologically distinct Na+ channels contribute to neuronal hyperexcitability that can produce clinically signi¢cant signs and symptoms This concept, and our meeting which will explore it, re£ects the convergence of a number of important themes: The ¢rst theme is channel diversity We are recognizing an increasing degree of diversity among Na+ channels We now understand that at least 10 di¡erent genes... types of channels b subunits are multiple and diverse, with an ensemble of functions and behaviours so rich that one investigator in this room has suggested that a subunits may be accessories to b subunits! The fourth theme is pathophysiology At this meeting we will be talking about the potential contributions of Na+ channels to neuronal hyperexcitability We will see that anomolously expressed Na+ channels. .. was originally assigned symbols SCN6A and SCN7A, which were mapped in human and mouse, respectively The two most likely represent the same gene, and the SCN6A symbol will probably be deleted Reproduced with permission from Goldin et al (2000) 4 WAXMAN The past decade has given us new drugs and toxins that modulate channels, and we are gaining an increased understanding of their mechanism of action We... genes encode molecularly distinct Na+ channels Interestingly, several cell-speci¢c Na+ channels have been identi¢ed, including Na+ channels that are preferentially expressed within dorsal root ganglion neurons and trigeminal neurons The molecular diversity of Na+ channels appears to be paralleled by diversity in terms of physiological and pharmacological properties, and in terms of functional roles We... domain IV of Na+ channels, three charges have to be transferred to reach the initial open state, and a fourth for fast inactivation to take place The single late openings in the inactivated steady state may be explained by the transfer of a ¢fth charge in IVS4, while the larger bursts of reopening involve a modulation of the mechanism of fast inactivation 2002 Sodium channels and neuronal hyperexcitability . SODIUM CHANNELS AND NEURONAL HYPEREXCITABILITY Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 2002 JohnWiley. 0-470-84668-2 Novartis Foundation Symposium 241 SODIUM CHANNELS AND NEURONAL HYPEREXCITABILITY 2002 JOHN WILEY & SONS, LTD Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright. production. Sodium Channels and Neuronal Hyperexcitability. Novartis 241 Copyright & 20 02 JohnWiley & Sons Ltd Print ISBN 0-471-48530-6 Online ISBN 0-470-84668-2 Contents Symposium on Sodiumchannels