Current Aspects of the Neurosciences Volume 2 Current Aspects of the Neurosciences Volume 2 Edited by Neville N. Osborne Nuffield Laboratory of Ophthalmology University of Oxford Oxford OX2 6A W, UK M MACMILLAN PRESS Scientific & Medical © The Macmillan Press Ltd 1990 Softcover reprint of the hardcover 1s t edition 1990 All rights reserved. No reproduction, copy or transmission of this publication may be made without written permission. No paragraph of this publication may be reproduced, copied or transmitted save with written permission or in accordance with the provisions of the Copyright, Design and Patents Act 1988, or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 33-4 Alfred Place, London WCIE 7DP. Any person who does any unauthorized act in relation to this publication may be liable to criminal prosecution and civil claims for damages. First published 1990 Published by THE MACMILLAN PRESS LID Houndmills, Basingstoke, Hampshire RG21 2XS and London Companies and representatives throughout the world Filmset by Wearside Tradespools, Fulwell, Sunderland British Library Cataloguing in Publication Data Current aspects of the neurosciences. Vol. 2 1. Man. Nervous system. Diseases I. Osborne, Neville N. (Neville Nahash) 1942- 616.8 ISBN 978-1-349-11924-0 ISBN 978-1-349-11922-6 (eBook) DOI 10.1007/978-1-349-11922-6 Contents Preface vii 1. Second Messengers in Neuronal Growth and Degeneration 1 M. P. Mattson 2. Receptors Linked to Hydrolysis of Choline Phospholipids: the Role of Phospholipase D in a Putative Mechanism of Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. . . 49 K. Loffelholz 3. Pertussis Toxin-sensitive GTP-binding Proteins in Neuronal Tissues: Recent Insights into Expression and Function . . . . . . . . . 77 G. Milligan 4. Regulation of Ion Channels and Neurotransmitter Release by Protein Kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 0. 9. . . P. J. Conn s. From Synapse to Genome: the Role of Intermediate-early Genes in Permanent Alterations in the Central Nervous System . . . . . . . . . 143 H. A. Robertson and M. Dragunow 6. Platelet-derived Products and Adrenergic Neurotransmission 159 T. J. Verbeuren 7. Control of Exocytosis in Secretory Cells: the Adrenal Chromaffin Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 191 A. J. O'Sullivan and R. D. Burgoyne 8. Neuropeptide Co-storage and Exocytosis by Neuronal Large Dense-cored Vesicles: How Good is the Evidence? . . . . . . . . . . . 2. 1. 9 R. L. Klein and A. K. Thureson-Klein vi Contents 9. Selective Ligands for Ber.zodiazapine Receptors: Recent Developments ........... ...... . . . . . . . . . . . . . . . . . . . . . 259. . . . . D. J. Nutt Index 295 Preface Current Aspects of the Neurosciences attempts to highlight new and fast moving areas in neuroresearch through the eyes of the involved investigators. Thus, although each chapter is written from a relatively personal point of view, it contains new, up-to-date material and ideas that should be of immediate interest to the reader as well as providing background information of longer-term, archival interest. It is also hoped that each chapter will provide an overview of a research area together with theoretical and practical guidelines for future work. Originally, the editor intended to produce the volumes annually. The immediate and positive response to Volume 1, however, has induced the editor to publish the volumes on a somewhat more rapid, albeit irregular, schedule. As stated in the Preface to the first volume, the ever-increasing amount of data in the neurosciences is difficult to absorb and interpret. The area of research related to the generation of second messengers and subsequent actions on enzymes, proteins, channels, oncogenes, secretory processes, growth and differentiation is of particular interest at the present moment. It is this field of research that provides the focal point of this volume. . Oxford, 1990 N.N.O . 1 Second Messengers in Neuronal Growth and Degeneration MARK P. MATTSON Sanders-Brown Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, KY 40536-0230, USA Contents 1. Introduction .... ..... '.' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2. Tools to investigate the regulation of neuroarchitecture . . . . . . . . . . . . . . . . . 5 3. Second messengers in the development of neural circuitry .. . . . . . . . . . . . . . 6 Calcium ........... ...................... ..... .................. 7 Inositol phospholipid metabolites . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . Cyclic AMP ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 4. . . . . . . . . . . . . Interactions between different second-messenger systems . . . . . . . . . . . . 15. Synaptogenesis and second messengers ............... ..... ......... 17 4. Second messengers and neuronal degeneration . . . . . . . . . . . . . . . . . . 2.0 . . . . Calcium and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 . . . . . . . Calcium-independent neurodegeneration ........................... 23 A role for second messengers in selective neuronal degeneration 26 Imbalances in cellular signalling: a common basis for age-and disease-related neurodegeneration? . . . . . . . . . . . . . . . . . . . . . . . 3. 0. . . . . . . 5. Emerging concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 2. . . . . . . . . . . . Control points within signal transduction pathways confer specificity on the regulation of neuroarchitecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 . . . . . . . Compartmentalization of signal transduction systems .. ....... ........ 34 Second messengers and therapeutic strategies for neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 0 . . . . . . . . . . . . . . 6. What next? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 .3 . . . . . . . . . . . . References ....................................... .................. 43 Current Aspects of the Neurosciences, Vol. 2. Edited by N. N. Osborne. © The Macmillan Press Ltd 1990 1 2 Mark P. Mattson 1. Introduction Just as different animal and plant species are identifiable by their particular shapes and sizes, different cell types also have identifying forms. For example, in the nervous system different types of nerve cells and glial cells are easily discriminated (Figure 1). The shapes of all animal cells are determined largely by two interacting systems, the cytoskeleton and the plasma mem brane. In general, the molecular compositions of these cellular building blocks are quite similar from cell type to cell type and from animal to animal. Thus, from yeast to man, cytoskeletal microfilaments are composed of essentially the same actin protein, and cell membranes possess similar phospholipid molecules. This conversion of cell structural components raises an intriguing question: If the building blocks of different cells are similar, then what accounts for the great diversity of cell shapes? One answer is that mechanisms exist for controlling the structural building blocks, and moulding them into their cell type-specific arrangements. The topic of this chapter concerns the intracellular signallinl!: mechanisms that control the architecture Figure I Cells in the nervous system have characteristic shapes, which are reliably generated in cell culture. (A) A hippocampal pyramidal neuron extends one long and ramifying axon, and several short dendrites. (B) An astrocyte identified by its polygonal shape; note that the flatness of this cell allows visualization of the nucleus (light circle in the cell centre) and the condensed chromatin within the nucleus (black region). (C) An oligodendrocyte identified as by its radial extensions of rather broad processes. Scale bars, 25 f.Lm Second Messengers in Neuronal Growth and Degeneration 3 of the fundamental cellular unit of the nervous system, the neuron. The remarkable ability of the nervous system to integrate complex environmental information and generate appropriate responses depends upon the underlying cellular structure of its neural circuits. Functional neural circuitry is determined, in large part, by what neurons are present, the shapes of their neuritic arbors, and the spatial arrangement of synapses between the different neurons. Together, these morphological features of neural circuitry constitute neuroarchitecture. In order for this neuroarchitecture to develop, a great deal of communication between cells must occur. Intercellular com munication involves molecules that exert their effects on neurite outgrowth and cell survival by binding to specific cell surface receptors. Three important classes of these molecules are neuronal growth factors, neurotransmitters and the molecules that mediate cell-substrate interactions. Neuronal growth factors include proteinaceous molecules such as nerve growth factor (NGF), ciliary-derived neurotrophic factor and fibroblast growth factor (FGF) (Green and Shooter, 1980; Varon et al., 1988; Walicke et al., 1986). Among the neurotransmitters known to influence neuroarchitecture are glutamate, serotonin, acetylcholine and GAB A (Mattson, 1988). Cell-binding proteins such as laminin, fibronectin and the neural-cell adhesion molecules (NCAMs) also interact with neurons through specific receptors (Jessell, 1988; Sanes, 1989). Developmental roles for these different signals have been supported by studies of neuronal outgrowth and survival both in situ and in cell culture. The present chapter considers the intracellular signalling pathways that transduce the event of ligand binding to a cell surface receptor into a morphological response, such as an alteration in neurite outgrowth or cell survival. The generally accepted definition of a 'second messenger' is a molecule that is liberated into the cytoplasm as a result of a ligand binding to a cell surface receptor, ahd that modifies substrate proteins usually by catalysing the transfer of a phosphate from a protein kinase to the substrate protein. Calcium, cyclic AMP and diacylglycerol are arguably the most prevalent and important second messengers in the animal kingdom. Throughout the present chapter I will refer often to second messenger 'systems', which can be considered as a series of steps prior to, and following the generation of the second messenger that leads to cellular response. In addition, the mechanisms whereby the cell inactivates (or removes) the second messenger are included in the second-messenger system. An important concept arising from studies of neuronal second messengers is that different environmental signals can act through similar or disparate second-messenger systems to attain a net effect on neuroarchitecture. Recent efforts in this lab have been directed at understanding such interactions between signalling systems. Some of these recent results are presented below. The second-messenger systems that transduce environmental signals ultimately influence the components of the neuronal cytoskeleton and vesicular systems that govern neuronal morphology. The cytoskeleton con-