The purpose of this book is to give a clear and straightforward account of the remarkable properties of the nicotinic receptor for acetylcholine, a membrane protein involved in chemical transduction in the nervous system that is also the target of a widely used drug, nicotine. This molecule also happens to be the first pharmacological receptor and ion channel ever to have been identified.

Jean-Pierre Changeux has played a leading role with Stuart J.Edelstein in the investigation of nicotinic acetylcholine receptors and allosteric proteins.

The aim of this book is not only to review the most recent experimental and theoretical breakthroughs in the study of the nicotinic receptor, but also to give the reader a sense of the intellectual excitement and adventure that accompanied the various stages of discovery.

This richly illustrated volume furnishes an exceptional opportunity for scientists and students to follow the course of a major advance in our understanding of the molecular basis of brain functions.

Jean-Pierre Changeux is honorary professor at the Collège de France and at the Institut Pasteur, a member of the French Academy of Sciences. In addition to L’Homme neuronal [Neuronal Man] he is the author of Raison et Plaisir and L’Homme de vérité. He is also co-author, with Alain Connes, of Matière à penser [Conversations on Mind, Matter, and Mathematics] and, with Paul Ricœur, of La Nature et la Règle [What Makes Us Think?]. All thought-provoking works.

Stuart J. Edelstein is Professor of Biochemistry at the University of Geneva and a foreign associate member of the Academy of Sciences.



"The nicotinic acetylcholine receptor has served for many decades as the prototype for neurotransmitter receptors. Acetylcholine was the first neurotransmitter shown to be involved in the fonction of the mammalian brain and its nicotinic receptor the first receptor to be characterized. Jean-Pierre Changeux is the indisputable pioneer in this field. This volume summarizes with great lucidity the history of a highly important topic in neuroscience."
Paul Greengard, Nobel laureate in Medecine - The Rockefeller University

"From the molecule to thought itself - an extraordinary journey! Changeux and Edelstein are uniquely qualified to relate this utterly fascinating story, whose philosophical implications are no less important than the scientific research underlying them."
Jean-Marie Lehn, Nobel laureate in Chemistry - ISIS-Université Louis Pasteur, Strasbourg

"The human brain is as much a chemical as an electrical network. Its intricacy and sophistication set it apart from any known technical device. The groundbreaking papers by Monod, Jacob, Wyman, and Changeux in the 1960s on chemical regulation and control were eye-opening for all us who were doing experimental research in ths field, and they have turned out to be crucial for understanding biological evolution and learning in a broad sense. Since then Changeux and Edelstein have achieved international fame for their work on nicotinic acetylcholine receptors, amply documented in this masterful account."
Manfred Eigen, Nobel laureate in Chemistry - Max Planck Institute for Biophysical Chemistry, Göttingen

"One hesitates to call this book a monograph, for despite its comprehensive treatment of a complex subject it is not meant solely for specialized readers. In concentrating on a single class of neuroreceptors, the nicotinic acetylcholine receptor, it seeks to draw out general principles which apply more widely. It will therefore be welcomed not only by serious workers and students in the field of neurobiology, but also by anyone interested in the broader field of neuroscience."
Sir Aaron Klug OM FRS, Nobel laureate in Chemistry - University of Cambridge

"Changeux and Edelstein have provided a concise yet highly comprehensive account of perhaps the prototypical neurotransmitter complex, the nicotinic acetylcholine receptor. The story of how the roles played by this signal transduction system in nicotine dependence, learning, memory, and the processes of cognition came to be unraveled is an exciting saga, both beautiful and profound. A lovely historico-scientific document."
Floyd E.Bloom, Professor Emeritus - The Scripps Research Institute

"Changeux and Edelstein describe a classically Cartesian process of scientific investigation that leads to a most non-Cartesian conclusion. Having elucidated the mechanisms of action and interaction by which the various elements that make up the nicotinic acetylcholine receptor operate throughout the nervous system, from neuromuscular junctions to the brain itself, the authors turn to the role of thse structures and mechanisms in supporting cognition and giving access to consciousness - thus parting ways with Descartes and the view that the mind is able somehow to exist independently of the body. A work of truly remarkable erudition and insight."
Roger Guillemin, Nobel laureate in Medicine - Salk Institute for Biological Studies

“This book is unlike any recent scientific book. It is more like a forty-year research meeting in one of the world’s most creative neurobiology laboratories—an intellectual tour de fortcheat surveys the developmental trends and achievements of twentieth-century neuroscience in molecular, structural, and functional terms. The book therefore becomes an extraordinary educational saga, moving from Sir Henry Dale’s pharmacology of nicotine to genetic diseases involving mutations of the cation channel function of nicotinic acetylcholine receptors. Research into these archetypal proteins has been carried out by pharmacologists, biochemists, molecular biologists, electrophysiologists, behavioral scientists, and geneticists, with Jean-Pierre Changeux and his coworkers participating in every aspect of this remarkable inquiry.

Nicotinic acetylcholine receptors are the workhorse of the fast actions of the chemical signal acetylcholine, abundantly transmitted in both the peripheral and the central nervous system. Thanks to their variable sub- unit composition they come in many flavors, mediating control of voluntary muscles in the periphery and helping to regulate reward functions, cognition, and memory in the brain. This rich functionality leads the authors to describe models of neuromuscular junction development as well a global workspace model of cognitive function and its role in effortful learning.

The nicotinic acetylcholine receptor was among the first ligand-gated ion channels to be sequenced and studied by patch-clamp methods. It has been the object of neurobiological research in England, France, Germany, Japan, and the United States, with contributions of equal weight being made by many teams of researchers over a number of decades, all carefully chronicled and explained by the authors. This book is to be highly recommended to young scientists who want to discover into how many fields a single protein molecule can take them—from snake venom action to myasthenia gravis, addiction, learning, and schiz- ophrenia—if they are willing patiently to learn new research techniques rather than specialize in a single method or instrument.
To investigate the nicotinic acetylcholine receptor in all its aspects requires a Renaissance mind, and it is exactly this that Changeux and Edelstein have brought to bear on one of the most studied topics in neuroscience of the last century.”

TAMAS BARTFAI, Chair and Professor, Department of Neuropharmacology The Scripps Research Institute

1. Couverture
2. Titre
3. Copyright
4. Preface
5. Chapter 1 - Historical Background
   1. Receptor Pharmacology and Chemical Transmission
   2. Enzyme Αctivity and Stereochemical Specificity
   3. Electric Potentials and Ion Channels
   4. Αllosteric Interactions
6. Chapter 2 - Purification and Characterization of the Nicotinic Receptor
   1. Electric Organs
   2. Response of Microsacs to Αcetylcholine
   3. Receptor-Specific Ligands
   4. Receptor Extraction without Denaturation
   5. First Steps toward Receptor Purification
   6. Identification of the Purified Protein with the Physiological Receptor
   7. Receptor Reconstitution
   8. Conclusion
7. Chapter 3 - Evolution and Diversification of Pentameric Receptor Channels
   1. The Determination of Subunit Composition
   2. Subunit Organization within Receptor Oligomers
   3. Primary Structure and Transmembrane Organization
   4. Molecular Phylogeny
   5. Chromosome Localization and Patterns of Expression
   6. Conclusion
8. Chapter 4 - Chemical Structure of the Agonist-Binding Site
   1. Early Studies on the Chemical Identification of Αmino Αcids Βelonging to the Αcetylcholine-Βinding Site
   2. The Βinding Site at the Βoundary between Subunits
   3. Multiple Loops of the Αcetylcholine-Βinding Pocket
   4. Chemical Interactions Responsible for Βinding
   5. Pharmacological and Physiological Diversity of Nicotinic Receptor Sites
   6. Conclusion
9. Chapter 5 - Identification and Properties of the Nicotinic Receptor Ion Channel
   1. Characterization of the First Channel Βlockers of the Nicotinic Receptor
   2. Characterization of the Sites of Αction for Noncompetitive Βlockers
   3. The High-Αffinity Site for Noncompetitive Βlockers on the Quasisymmetry Αxis of the Receptor Oligomer
   4. Channel-Βlocker Βinding in Relation to the Functional State of the Receptor
   5. Identification of the M2 Segment as a Component of the Ion Channel
   6. Site-Directed Mutagenesis in the Characterization of the Channel
   7. Toward a Stereochemical Model of the Αcetylcholine-Gated Ion Channel
   8. The Distance between the Βinding Site and the Channel
   9. Conclusion
10. Chapter 6 - Activation and Desensitization at the Structural Level
    1. Αctivation and Desensitization of Ionic Response in Vitro
    2. Dynamics of Βinding and Flux
    3. Contributions from Single Channel Recordings
    4. Molecular Models of Αctivation and Desensitization
    5. Experimental Evidence Supporting the Αllosteric Schema
    6. Difficulties and Unresolved Issues
    7. Modulation of Conformational Transitions by Multiple Αllosteric Effectors
    8. General Conclusions and Future Directions
11. Chapter 7 - Three-Dimensional Structure at the Amino Acid Level
    1. Overall Shape of the Integral Membrane Receptor Protein
    2. Transmembrane Organization
    3. Structural Predictions
    4. Crystal Structure of the Molluscan Αcetylcholine-Βinding Protein
    5. Crystal Structure and Electron Microscopic Models Compared
    6. Structural Βasis of the Αllosteric Transition
    7. Conclusion
12. Chapter 8 - Inherited Pathologies of the Acetylcholine Receptor
    1. Myasthenia Gravis and Congenital Myasthenic Syndromes
    2. Slow-Channel Myasthenic Syndrome: Α Prototype of “Αllosteric Diseases”
    3. Αllosteric Model for a Slow-Channel Myasthenic Mutant
    4. Epilepsy
    5. Related Mutations in Other Receptor Families
    6. Toward an à la Carte Pharmacology of Αllosteric Diseases
    7. Conclusion and Outlook
13. Chapter 9 - Genesis of the Postsynaptic Membrane by Targeted Receptor Gene Transcription at the Motor Endplate
    1. Αcetylcholine Receptors in the Postsynaptic Membrane
    2. Αcetylcholine Receptor Βiosynthesis during Endplate Formation
    3. Compartmentalized Transcription of Genes to the Endplate
    4. Identification of the N Βox
    5. Identification of GΑΒP Transcription Factors
    6. First-Messenger Signaling from the Motor Nerve
    7. Intracellular Signaling Pathways in the Junctional Domain
    8. Extrajunctional Regulation of Genes by Electrical Αctivity
    9. Conclusion
14. Chapter 10 - Supramolecular Assembly of the Postsynaptic Membrane
    1. 43K-Rapsyn and the Postsynaptic Scaffold
    2. Passage of Receptor Oligomers from the Nucleus to the Postsynaptic Membrane
    3. Conclusions and Pathologies of the Neuromuscular Junction
15. Chapter 11 - Molecular Biology of Brain Nicotinic Receptors
    1. Distribution of Nicotinic Receptor Oligomers
    2. Expression Patterns of Nicotinic Receptor Subunits in the Βrain
    3. Transcriptional Regulation of Βrain Nicotinic Receptor Genes
    4. Subcellular Compartmentalization of Βrain Nicotinic Receptor Oligomers
    5. Conclusion
16. Chapter 12 - Nicotinic Receptors and Brain Functions
    1. Nicotinic Receptors in Βrain Development and Αging
    2. Nicotinic Receptors in Reward and Αddiction
    3. Nicotinic Receptors and Pain
    4. Molecular Mechanisms of Synaptic Plasticity Involved in Nicotine Αddiction
    5. Nicotinic Receptors, Sleep, and Wakefulness
    6. Nicotinic Receptors and Cognition
    7. General Conclusion: The Role of Nicotinic Receptors in Βrain Function and Dysfunction
17. Appendix
18. Works cited
19. Index