Ernst Schering Research Foundation Workshop 23 Excitatory Amino Acids

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1 Ernst Schering Research Foundation Workshop 23 Excitatory Amino Acids

2 Springer-Verlag Berlin Heidelberg GmbH

3 Ernst Schering Research Foundation Workshop 23 Excitatory Amino Acids From Genes to Therapy P. H. Seeburg, I. Bresink, L. Turski Editors With 45 Figures in 125 Separate Illustrations Springer

4 Series Editors: G. Stock and D.-F. Habenicht ISSN ISBN ISBN (ebook) DOI / CIP data applied for Die Deutsche Bibliothek - CIP-Einheitsaufnalune Schering-Forschungsgese1lschaft <Berlin>: Ernst Schering Research Foundation Workshop. - Berlin; Heidelberg; New York; Barcelona; Budapest; Hong Kong; London; Milan; Paris; Santa Clara; Singapore; Tokyo: Springer. ISSN Excitatory amino acids: from genes to therapy Excitatory amino acids: from genes to therapy / P.H. Seeburg... ed. - Berlin; Heidelberg; New York; Barcelona; Budapest; Hong Kong; London; Milan; Paris; Santa Clara; Singapore; Tokyo: Springer (Ernst Schering Research Foundation Workshop; 23) This work is subject to copyright. All rights are reserved. whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer -Verlag Berlin Heidelberg 1998 Originally published by Springer-Verlag Berlin Heidelberg New York in Softcover reprint of the hardcover I st edition 1998 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: TBS, Sandhausen SPIN: / Printed on acid-free paper

5 Preface Glutamate Antagonists: Quo Vade? Since the beginning of the 1990s, glutamate antagonists have repeatedly excited the scientific community through discoveries of their intriguing role in physiology and pathology. Until today they have remained the major hope for the therapy of neurodegenerative disorders in humans. NMDA antagonists have been designed for the treatment of acute-onset neurodegeneration such as stroke and trauma, and have recently reached the clinics. Unfortunately, the anticipated success of NMDA antagonists in patients has been limited due to unacceptable side effects. In the meantime, AMP A antagonists have left the realm of drug research and are rapidly moving towards the clinic. The expectations and medical needs, which have changed little over time, are placing development of AMP A antagonists under public attention. The enthusiasm which surrounds AMPA antagonists is great, since they appear to be safer and to have fewer side effects than the NMDA antagonists. Research on glutamate receptors has entered the phase of discovering molecular details of the channels and genetic principles, which determine phenotypic characteristics and sensitivity of neurons to the deleterious influences of nature. The engineering of transgenic mice with modified expression of single-receptor subunits has enabled insights into the function, dysfunction, and possible pathology causally related to glutamate receptors.

The entry of AMP A antagonists into the clinic for first evaluations in humans dominates the field of today's glutamate research.

6 VI Preface The participants of the workshop The meeting on "Excitatory Amino Acids: From Genes to Therapy" addresses today's emerging questions and discusses new avenues which glutamate research may take in the future. The entry of AMP A antagonists into the clinic for first evaluations in humans dominates the field of today's glutamate research. The picture of kainate receptors is slowly emerging and coming into focus. These enigmatic receptors may dominate the field soon, leading to new excitements and novel research efforts. P. H. Seeburg l. Bresink L. Turski

7 Table of Contents Glutamate Receptor Channels, RNA Editing, and Epilepsy P.H. Seeburg, R. Brusa, M. Higuchi, and R. Sprengel 2 Regulation of Glutamate Receptor Gene Expression in Global Ischemia D.E. Pellegrini-Giampietro Factors Regulating Excitotoxic Neurodegeneration: The Role of Calcium and the Mitochondria R.I. Miller, V.P. Bindokas, D.F. Babcock, J.-P. Lee, and J.B. Jordan Excitotoxicity, Genetics, and Neurodegeneration in Amyotrophic Lateral Sclerosis P.l. Shaw NO-NMDA Receptor Interactions: A Neuromolecular Approach to Novel Therapeutics S.A. Lipton, Y.-B. Choi, N.J. Sucher, and H.S.-V. Chen 95 6 Glutamate in Neurodegenerative Disorders: Phenotype Resulting from Decreased Expression of AMPA Receptor GluR-B Subunit mrna in Rats G. Miiller, U. Endermann, I. Bresink, and L. Turski

8 VIII Table of Contents 7 Quantitative Estimation of NMDA Receptor-Mediated Ca 2 + Entry in Central Neurons O. Caraschuk, T. Plant, and A. Konnerth Calcium Permeability of Glutamate-Gated Channels in the CNS: Functional Role of the cl+ -Permeable AMP A Receptor Channels N. Burnashev Localisation and Surface Expression of the AMP A Receptor Subunit GluRI Using Green Fluorescent Protein and Anti-Peptide Antibodies A. Doherty, A. Irving, C.L. Colling ridge, and 1.M. Henley Input- and Output-Specific Segregation of Amino Acid Neurotransmitter Receptors on the Surface of Central Neurones Z. Nusser and R. Shigemoto 187 Subject Index Previous Volumes Published in this Series

9 List of Editors and Contributors Editors P.H. Seeburg Max Planck Institute for Medical Research, Department of Molecular Neuroscience, Jahnstr. 29, Heidelberg, Germany I. Bresink Research Laboratories of Schering AG, Miillerstr. 178, l3342 Berlin, Germany L. Turski Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, London WC1E 6BT, UK Contributors D.F. Babcock Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 East 58th Street (MC 0926), Chicago, IL 60637, USA I. Bresink Research Laboratories of Schering AG, Miillerstr. 178, Berlin, Germany V.P. Bindokas Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 East 58th Street (MC 0926), Chicago, IL 60637, USA

10 x List of Editors and Contributors R. Brusa Schering Plough Research Institute, Via Olgettina 58, Milan, Italy N. Burnashev Max-Planck-Institute of Medical Research, Department of Cell Physiology, Jahnstr. 29,69120 Heidelberg, Germany H.S.-V. Chen CNS Research Institute, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue-LMRC, Boston, MA 02115, USA Y.-B. Choi CNS Research Institute, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue-LMRC, Boston, MA 02115, USA G.L. Colling ridge Department of Anatomy, Medical School, University of Bristol, Bristol, BS8 ltd, UK A. Doherty Department of Anatomy, Medical School, University of Bristol, Bristol, BS8ITD, UK U. Endermann Research Laboratories of Schering AG, Miillerstr. 178, Berlin, Germany o. Garaschuk Institute of Physiology I, University of Saarland, Homburg, Germany 1.M. Henley Department of Anatomy, Medical School, University of Bristol, Bristol, BS8 ltd, UK M. Higuchi Max Planck Institute for Medical Research, Department of Molecular Neuroscience, Jahnstr. 29, Heidelberg, Germany A. Irving Department of Biomedical Sciences, Institute of Medical Sciences, Forrester Hill, University of Aberdeen, Aberdeen, AB25 2ZD, UK

11 List of Editors and Contributors XI J.B. Jordan Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 East 58th Street (MC 0926), Chicago, IL 60637, USA A. Konnerth Institute of Physiology I, University of Saarland, Homburg, Gennany J.-P. Lee Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 East 58th Street (MC 0926), Chicago, IL 60637, USA S.A. Lipton CNS Research Institute, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue-LMRC, First Floor, Boston, MA 02115, USA R.J. Miller Department of Phannaco1ogical and Physiological Sciences, The University of Chicago, 947 East 58th Street (MC 0926), Chicago, IL 60637, USA G. Maller, Neurology Research, Warren 407, Massachusetts General Hospital, Harvard Medical School, Fruit Street, Boston, MA 02114, USA Z. Nusser Medical Research Council, Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK D.E. Pellegrini-Giampietro Department of Preclinical and Clinical Pharmacology "Mario Aiazzi Mancini", University of Florence, Viale G.B. Morgagni 65,50134 Florence, Italy T. Plant Institute of Physiology I, University of Saarland, Homburg, Gennany P.H. Seeburg Max Planck Institute for Medical Research, Department of Molecular Neuroscience, Jahnstr. 29, Heidelberg, Germany

12 XII List of Editors and Contributors P.l. Shaw Department of Clinical Neurology, Royal Victoria Infirmary, University of Newcastle upon Tyne, Newcastle upon Tyne NEI 4LP, UK R. Shigemoto Medical Research Council, Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OXI 3TH, UK, and Department of Morphological Brain Science, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan R. SprengeZ Max Planck Institute for Medical Research, Department of Molecular Neuroscience, Jahnstr. 29, Heidelberg, Germany N.J. Sucher CNS Research Institute, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue-LMRC, Boston, MA 02115, USA L. Turski Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, London WClE 6BT, UK

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