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.

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