Acetylcholine, a Ubiquitous Signalling Substance Acetylcholine, a Ubiquitous Signalling Substance By Yves Dunant Acetylcholine, a Ubiquitous Signalling Substance By Yves Dunant This book first published 2021 Cambridge Scholars Publishing Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Copyright © 2021 by Yves Dunant All rights for this book 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, recording or otherwise, without the prior permission of the copyright owner. ISBN (10): 1-5275-6721-4 ISBN (13): 978-1-5275-6721-4 This book is dedicated to Annemarie and to our children and grandchildren We cannot change the reality according to our ideas, but we can change our ideas according to reality, some people can, at all events. —Fridjof NANSEN, neurobiologist, explorer, Nobel Peace Prize Whenever a new discovery is reported to the scientific word, they say first: “It is probably not true.” Thereafter, when the truth of the proposition has been demonstrated beyond question, they say: “Yes, it may be true, but it is not important.” Finally, when sufficient time has elapsed to fully evidence its importance, they say: “Yes, surely it is important, but it is no longer new.” —Attributed to Michel de MONTAIGNE Eppure si muove ! —Attributed to GALILEO TABLE OF CONTENTS List of Figures............................................................................................ xi Acknowledgements .................................................................................. xii Introduction ............................................................................................. xiii Abbreviations ........................................................................................... xv Chapter 1 .................................................................................................... 1 Acetylcholine: a Ubiquitous Messenger Acetylcholine in primitive organisms ................................................... 1 Acetylcholine in plants ......................................................................... 2 Conclusion ............................................................................................ 2 Chapter 2 .................................................................................................... 3 Extraneuronal Acetylcholine Signalling Cholinergic signalling in the vascular endothelium .............................. 3 Digestive, urinary and respiratory systems ........................................... 4 Cholinergic immune cells ..................................................................... 6 Acetylcholine in the skin and the corneal epithelium ........................... 6 Non-synaptic ACh in the myoskeletal system ...................................... 7 Acetylcholine and reproduction ............................................................ 7 Cholinergic cell lines ............................................................................ 8 ACh synthesis, release and hydrolysis in the non-neuronal cholinergic system .............................................................................................. 9 Conclusions and perspectives ............................................................... 9 Chapter 3 .................................................................................................. 11 Extra-synaptic Acetylcholine Signalling in Nervous Systems Diffuse cholinergic transmission in the autonomic nervous system .. 11 Quantal acetylcholine release from Schwann cells at the denervated neuromuscular junction ................................................................. 12 “Volume transmission” in the central nervous system ........................ 12 Conclusion and perspectives ............................................................... 14 viii Table of Contents Chapter 4 .................................................................................................. 15 Cholinergic Neuro-neuronal Synapses Sympathetic ganglions ........................................................................ 15 Electrical versus humoral nature of transmission: a famous controversy .................................................................................... 18 Synaptic transmission in parasympathetic ganglions .......................... 19 Neuro-neuronal cholinergic synapses in the central nervous system .. 22 Conclusions and perspectives ............................................................. 23 Chapter 5 .................................................................................................. 24 Ultra-rapid Cholinergic Synapses The vertebrate neuromuscular junctions (NMJs) ................................ 24 The fish nerve-electroplaque junctions (NEJs) ................................... 27 Transmission in neuromuscular and nerve-electroplaque junctions is ultra-fast and highly synchronised................................................. 32 ACh quantum, the unit of transmission in rapid cholinergic synapses 33 ACh subquantum, the subunit of transmission in rapid cholinergic synapses and the unit of transmission in other synapses .............. 34 Transmitter quanta, subquanta and synaptic vesicles .......................... 37 Ca2+ sparks and Ca2+ quarks in the heart: a model for ACh quanta and subquanta in synapses? .................................................................. 38 Chapter 6 .................................................................................................. 39 Voltage-gated K+ Channels Curtail the Presynaptic Action Potential The three mechanisms that make neuromuscular transmission so rapid .......................................................................................... 39 A giant potential is generated in response to a single stimulus after blockade of presynaptic K+ channels............................................. 40 Chapter 7 .................................................................................................. 43 Dynamics of Acetylcholine Compartments During Activity Functional pools of acetylcholine in sympathetic ganglions and other synapses ........................................................................................ 44 Preferential release of the newly synthesised ACh ............................. 46 Surplus ACh in anticholinesterase-treated preparations ..................... 46 The Torpedo electric organ brings new insights in the field ............... 47 Experiments on isolated cholinergic nerve terminals and synaptosome ghosts ....................................................................... 50 More about the vesicular pool of acetylcholine .................................. 52 Acetylcholine compartments analysed at a high time resolution ........ 52 Acetylcholine compartments in invertebrate cholinergic synapses .... 53 Acetylcholine, a Ubiquitous Signalling Substance ix Conclusion and perspectives ............................................................... 53 Chapter 8 .................................................................................................. 55 Morphological Changes Accompanying Acetylcholine Release Counting synaptic vesicles .................................................................. 55 Exocytosis images in rapid cholinergic synapses ............................... 56 Vesicle fusion captured by rapid cryofixation .................................... 57 Discrepancies between ACh release and vesicle fusion ...................... 58 The fleeting appearance of a population of large intramembrane particles is the constant morphological counterpart of quantal ACh release ................................................................................... 59 Significance of the fleeting particle change in the presynaptic membrane ...................................................................................... 62 Conclusions and perspectives ............................................................. 64 Chapter 9 .................................................................................................. 65 Involvement of the Mediatophore Proteolipid in ACh Release Mediatophore discovery, isolation, reconstitution and characterisation ............................................................................. 65 Reconstitution of Ca2+-dependent and quantal release upon mediatophore transfection ............................................................. 66 Mediatophore localisation ................................................................... 70 Mediatophore activation and transient occurrence of intramembrane particles ......................................................................................... 70 Mediatophore, a member of the proteolipid complexes produced by the ATP6V0C gene .................................................................. 71 A tentative model for the structural organisation of the mediatophore ................................................................................. 72 Proteolipids of the ATP6V0C gene proposed as possible tools for gene or cell therapy in neurodegenerative diseases ................. 72 Conclusions and perspectives ............................................................. 73 Chapter 10 ...............................................................................................