The Cholinergic Synapse

I. Model Cholinergic Systems.- 1: Model Cholinergic Systems: An Overview.- A. The Value of Model Systems.- B. Pros and Cons of Selected Model Systems.- I. Cephalopod Optic Lobe.- II. Electric Organs.- III. Myenteric Plexus-Longitudinal Muscle Preparation.- IV. Ganglion Preparations.- V. Mammalian Central Nervous System Preparations.- VI. Amphibian and Mammalian Voluntary Muscle.- References.- 2: Model Cholinergic Systems: The Electromotor System of Torpedo.- A. Embryology.- B. Components of the Electromotor System.- I. Electric Lobe.- II. Axons.- III. Electric Organ.- C. Conclusions.- References.- 3: Model Cholinergic Systems: The Avian Ciliary Ganglion.- A. Introduction.- B. Anatomy.- C. Electrophysiology and Biochemistry.- I. Chemical and Electrical Components in Synaptic Transmission.- II. Presence of Neuropeptides and its Implications.- III. Presence of Presynaptic ACh Receptors.- IV. Postsynaptic Receptor Heterogeneity.- V. Regulation of ACh Synthesis.- D. Cell and Tissue Culture.- E. Concluding Remarks.- References.- II. Biology of the Cholinergic Synapse.- 4: Phylogeny of the Cholinergic Synapse.- A. Introduction.- B. Variation at the Synaptic Level.- I. Parameters Considered.- II. Synthesis of ACh.- III. Termination of the Action of ACh.- IV. Characteristics of ACh Receptors.- C. Qualitative and Quantitative Changes in Cholinergic Innervation.- I. Qualitative Changes.- II. Quantitative Changes.- D. Conclusions.- References.- 5: Development of the Cholinergic Synapse: Role of Trophic Factors.- A. Introduction.- B. Parasympathetic Ciliary Neurons.- I. Ciliary Ganglion as a Model System.- II. Necessity of Trophic Factors for the Survival and Growth of Ciliary Neurons In Vitro.- III. Developmental Regulation of Survival Activity for Ciliary Neurons.- IV. Characterization of Ciliary Neuron Survival Factors.- V. Factors Affecting the Growth and Development of Ciliary Neurons In Vitro.- VI. Factors Stimulating Neurite Growth in Ciliary Neuron Cultures.- C. Spinal Cord Neurons.- I. Greater Complexity of the System.- II. Survival Factors for Spinal Cord Neurons.- III. Factors Stimulating ChAT Activity in Spinal Cord Cultures.- IV. Factors Stimulating Neurite Growth in Spinal Cord Cultures.- D. Sympathetic Neurons.- I. Evidence for a Cholinergic Subpopulation.- II. Induction of Cholinergic Transmitter Status in Sympathetic Neurons.- III. Characterization of the Cholinergic-Specifying Factor.- E. Conclusions.- References.- III. Molecular Components of the Cholinergic System.- 6: Estimation of Acetylcholine and Choline and Analysis of Acetylcholine Turnover Rates In Vivo.- A. Introduction.- B. Preparation of Samples for ACh and Choline Analysis.- I. General Requirements for Measurement of ACh and Choline.- II. Extraction of ACh and Choline from Tissues, Subcellular Fractions and Perfusates.- III. Preservation of ACh and Choline Post-Mortem.- C. Analysis of ACh and Choline.- I. Bioassay.- II. Chemical Techniques Before 1972, Excluding Radioenzymatic and Gas Chromatographic (GC) Assays.- III. Radioenzymatic Assays.- IV. GC and GCMS Analyses.- V. New Developments Since 1978.- D. Methods for Measuring ACh Turnover.- I. General Considerations.- II. Non-isotopic Methods.- III. Isotopic Methods.- E. Concluding Remarks.- References.- 7: Choline Acetyltransferase and the Synthesis of Acetylcholine.- A. Introduction.- B. Choline Acetyltransferase.- I. The Enzyme Molecule.- II. Catalytic Action.- III. Cellular and Subcellular Localization.- C. Supply of Substrates.- I. Acetylcoenzyme A.- II. Choline.- III. Source of Choline for ACh Synthesis.- D. Regulation of ACh Synthesis.- I. Kinetic Considerations.- II. Regulatory Factors.- References.- 8a: Vertebrate Cholinesterases: Structure and Types of Interaction.- A. Introduction.- B. Duality of ChEs: AChE and BuChE.- C. Molecular Forms of ChEs: The Value and Limitations of a General Scheme and a Nomenclature for Their Quaternary Structure.- D. Electric Organs of Fish: A Privileged Source of AChE for Biochemical Studies.- E. Quaternary Structure and Interactions of Asymmetric Forms.- I. Electrophorus.- II. Torpedo.- III. Asymmetric AChE Forms from Other Species, BuChE Asymmetric Forms, Hybrid AChE-BuChE Asymmetric Forms.- IV. Ionic Interactions.- V. Asymmetric AChE Forms and the Basal Lamina.- F. Physiochemical Properties of Globular Forms.- I. Solubility and Hydrophobicity: Operational Definition of Amphiphilic Molecules.- II. Solubility of ChE Globular Forms: Soluble and Detergent-Soluble Fractions.- III. Non-amphiphilic or Hydrophilic Globular Forms.- IV. Membrane-Bound, Intracellular and Extracellular Amphiphilic Forms.- V. Interactions with Detergent Micelles.- VI. Dimeric Forms Containing a Hydrophobic Glycolipid Anchor.- VII. Structure of G4 Forms Containing a Distinct Hydrophobic Subunit.- VIII. Solubilization Artefacts, Modifications of the Solubilized Forms.- IX. Catalytic Activity and Hydrophobic Interactions.- X. Thermal Stability.- G. Variability of the Catalytic Subunits.- I. Catalytic Subunits of AChE and BuChE in Vertebrates: Analysis by SDS-PAGE.- II. Specificity of Inhibitory Antibodies and Peptide Toxins.- III. Comparison Between Catalytic Subunits of Different AChE Fractions Within a Given Species.- IV. Heterogeneity of AChE Globular Forms in Non-denaturing Electrophoresis.- V. Binding of Lectins and Heterogeneity of Glycosylation of AChE Molecules.- H. Immunochemical Studies.- I. Immunochemical Cross-Reactivity Between AChE and BuChE.- II. Interspecific Cross-Reactivity.- III. Immunochemical Differences Between AChE Fractions Within a Given Organism.- I. Molecular-Biological Studies.- I. Characterization of AChE mRNAs and Their Translation Products.- II. Characterization of AChE cDNA Clones.- III. Primary Structures of ChEs.- J. Conclusions.- References.- 8b: Cholinesterases: Tissue and Cellular Distribution of Molecular Forms and Their Physiological Regulation.- A. Introduction.- B. Tissue Distribution of ChE Molecular Forms.- I. General Considerations.- II. Distribution of AChE Molecular Forms at Neuromuscular Junctions.- III. Ganglionic Synapses of the Autonomic Nervous System.- C. Subcellular Distribution of AChE Molecular Forms in Muscle and Nerve Cells.- I. Determination of Endo- and Ectocellular Enzyme Activities.- II. Distribution of Molecular Forms in Ecto- and Endocellular Compartments.- D. Biosynthesis and Renewal of AChE Molecular Forms.- I. In Vitro Studies.- II. Nervous Tissue and Muscle In Vivo.- E. Intracellular Transport and Secretion of AChE Molecular Forms.- I. Intracellular Transport.- II. Secretion.- F. Regulation of the Synthesis of AChE by Muscle and Nerve Cells During Development In Vivo and In Vitro.- I. Evolution of AChE Activity and Molecular Forms in Muscle and Nerve Cells During Embryogenesis.- II. Relationship Between Synthesis of A Forms and Innervation of Muscle and Nerve Cells In Vivo.- III. Regulation of the Synthesis of A Forms by Muscle and Nerve Cells In Vitro.- IV. Localization of AChE on Muscle Membranes.- G. Non-cholinergic Functions of ChEs.- I. Adult Tissues: New Substrates for ChEs.- II. “Embryonic ChE”: A Cholinergic Function in the Absence of Innervation?.- H. Effects of Peptides on ChEs.- I. Effect on the Activity of AChE.- II. Effect on the Synthesis of ChE.- I. ChEs in Pathological States and Their Evolution with Aging.- I. Muscular Dystrophy.- II. Human Pathology.- III. AChE and the Prenatal Diagnosis of Neural Tube Defects.- IV. Aging.- J. Conclusion.- References.- 9: Structure and Function of the Nicotinic Acetylcholine Receptor.- A. Introduction and Scope.- B. Structure of the nAChR.- I. Primary Structure.- II. Secondary Structure and Topography.- III. Tertiary Structure.- IV. Quaternary Structure.- V. Functional Domains.- VI. Conformations.- VII. Classification of ACh Receptors According to Structure.- C. Molecular Genetics.- I. Structure of nAChR Genes.- II. nAChR Gene Expression and Processing.- D. Function of the nAChR.- I. Ligand Binding.- II. Channel Gating.- III. Modulation of Binding and Response.- IV. Molecular Mechanism of Function.- References.- 10: Muscarinic Acetylcholine Receptors.- A. Introduction.- I. Two Main Types of ACh Receptor.- II. Biochemistry of mAChRs.- III. Localization of mAChRs.- B. Assays of Muscarinic Receptors and Muscarinic Ligands.- I. Binding Studies.- II. Assay of Muscarinic Agonist and Antagonist Actions.- III. Muscarinic Agonist Effects in Intact Animals.- C. Clinical Application of Muscarinic Drugs.- I. Therapeutic Uses of Muscarinic Drugs.- II. Acute Poisoning with Muscarinic Agonists.- III. Acute Poisoning with Muscarinic Antagonists.- References.- IV. Cellular Organization of the Cholinergic System.- 11: Cholinergic Synaptic Vesicles.- A. Introduction.- B. Isolation of Cholinergic Synaptic Vesicles.- C. General Properties.- D. Vesicle Core.- I. Constituents of the Core.- II. ACh and ATP.- III. Metal Ions.- IV. pH and Membrane Potential.- V. Proteoglycan.- VI. Peptides.- E. Vesicle Membrane.- I. Composition.- II. Membrane Lipids.- III. Polypeptide Composition.- IV. Vesicular Proteins.- F. Vesicular Transport Systems.- I. Types of System Present.- II. Vesicular Proton Pump.- III. Vesicular Uptake of Ca2+.- IV. Vesicular Uptake of Opioid Peptides.- V. Vesicular Uptake of ATP.- VI. Vesicular Uptake of ACh.- G. Dynamic Properties of Synaptic Vesicles.- I. Morphological Alterations on Nerve Stimulation.- II. Biochemical Alterations on Nerve Stimulation.- III. Mechanism of Exocytosis.- IV. Gated Release of ACh.- V. Life-Cycle of the Synaptic Vesicle.- References.- 12: Isolation of Cholinergic Nerve Terminals.- A. Introduction.- B. Historical Aspects.- C. Heterogeneous Mammalian Nerve-Terminal Preparations.- D. Heterogeneous Non-mammalian Nerve Terminals.- E. Purely Cholinergic Nerve-Terminal Preparations from Electric Organs.- I. Types of Preparation Available.- II. Purity and Functional State of Electromotor Synaptosome Preparations.- III. Presynaptic Plasma Membranes.- F. Affinity Purification of Mammalian Cholinergic Nerve Terminals.- I. Separation Procedure.- II. Characteristics of the Preparation.- G. Summary.- References.- 13: Axonal Transport in Cholinergic Neurons.- A. Introduction.- B. General Protein Transport in Cholinergic Nerves.- C. Transport of Distinctive Components of the Cholinergic Neuron.- I. Acetylcholine.- II. Acetylcholinesterase.- III. Choline Acetyltransferase.- IV. Cholinergic Synaptic Vesicle-Associated Proteins.- D. Interpretation of the Transport of Cholinergic-Specific Substances in the Context of General Axonal Protein Transport.- References.- 14: The High-Affinity Choline Uptake System.- A. Introduction.- B. Characteristics of HACU.- I. Tissue and Site Specificity.- II. Physiological Significance.- III. Structure-Activity Relationship Studies.- IV. Bioenergetics of Uptake.- V. Possible Role of Sialocompounds, Lipids and Steroids.- C. Identification of the HACU System.- I. Criteria for Identification.- II. Attempted Identification of Presynaptic Plasma Membrane Components and Their Modification.- III. Binding of Hemicholinium-3.- IV. Labelling with Covalent Probes.- V. Reconstitution of Choline Uptake Activity.- D. Areas for Future Investigation.- I. Functional Ligands and Components.- II. Arrangement of Transport System in the Membrane.- III. Isolation of Transport System.- IV. Possible Role of Lipids.- V. Conformational Changes of the Transporter Associated with Choline Uptake.- References.- 15: Cholinergic-Specific Antigens.- A. Introduction.- I. General Strategy.- II. The Problem of Unwanted Antibodies.- III. Complement Lysis Test.- B. Surface Antigens Specific for Cholinergic Nerve Terminals.- I. Identification of Cholinergic-Specific Gangliosides.- II. Applications of Anti-Chol-1 Antisera.- III. Possible Functional Significance of Chol-1.- IV. Complement-Mediated Lysis of Synaptosomes Induced by Anti-ChAT Antisera.- C. Synaptic Vesicle Proteoglycans.- I. From Torpedo marmorata.- II. From Other Torpedine Fish.- References.- 16: Cholinergic False Transmitters.- A. Definition and Structural Requirements.- I. Definition.- II. Adrenergic System.- III. Cholinergic System.- B. Differential Labelling of Transmitter Pools by False Transmitters.- I. Electric Organ.- II. Mammalian Preparations.- C. Conclusions.- References.- 17: Cholinergic Co-transmitters.- A. Introduction.- I. Scope of the Chapter: ATP and Neuropeptides.- II. Terminology.- III. Criteria to Be Satisfied.- B. ATP as a Neuroactive Compound.- I. ATP and Its Derivatives in Neuronal Function.- II. ATP in Chromaffin Granules.- III. ATP in the Cholinergic System of Torpedo.- IV. ATP in Mammalian Cholinergic Systems.- V. The Concept of Independent Purinergic Terminals.- VI. Must ATP Be Reckoned as a Cholinergic Co-transmitter?.- C. Evidence for Co-localization of Certain Neuropeptides and ACh.- I. Discovery of Neuropeptides.- II. Discovery of Co-localization.- III. Histochemical and Cytochemical Evidence for Co-localization.- IV. Cell-Biological and Biochemical Evidence.- V. Physiological and Pharmacological Evidence.- VI. Consequences of Coexistence of ACh and Neuropeptides.- References.- V. Peripheral Cholinergic Synapses.- 18: The Neuromuscular Junction.- A. Introduction.- B. Quantal Basis of Transmitter Release.- A. Classes of Quanta.- I. Bell-mEPPs and Skew- (sub-)mEPPS.- II. Schwann-Cell mEPPs.- III. Giant mEPPs and Doublet mEPPs.- IV. Slow Skew-mEPPs.- B. Subunit Hypothesis of the Quantum of Transmitter Release.- C. Morphological Correlates of Bell-mEPPs and Skew-mEPPs.- E Concluding Remarks.- References.- 19: The Electromotor Synapse.- A. Introduction.- B. Gross Physiology.- C. Physiology of Single Electrocytes.- D. Microphysiology of Transmission at the EMJ.- I. Extracellular Electroplaque Currents.- II. Intracellular Electroplaque Potentials.- III. Quantal Analysis of Electroplaque Potentials.- E. Conclusions.- References.- 20: The Autonomic Cholinergic Neuroeffector Junction.- A. Introduction.- B. Release of ACh.- I. Resting Release.- II. Electrically Evoked Release.- III. Release of Vasoactive Intestinal Peptide as a Co-transmitter in Cholinergic Nerves.- C. Modulation of ACh Release by Muscarinic Autoreceptors.- I. Prejunctional Autoreceptors.- II. Soma-Dendritic Autoreceptors.- D. Effects of ACh on Effector Organs: Mediation Through Subtypes of mAChRs.- References.- VI. Central Cholinergic Systems.- 21: Central Cholinergic Pathways: The Biochemical Evidence.- A. Introduction.- B. Biochemical Markers.- C. Preparation of Tissue.- I. Single Cell Preparations.- II. Microdissection from Freeze-Dried Sections.- III. Micropunches from Frozen Sections.- IV. Micropunches from Fresh Tissue.- V. Lesions.- D. Distribution of Cholinergic Markers in the Brain.- E. Localization of Cholinergic Pathways in the Brain.- I. Olfactory Bulb.- II. Cerebral Cortex.- III. Hippocampal Region.- IV. Amygdaloid Complex.- V. Striatum.- VI. Thalamus.- VII. Habenulo-Interpeduncular System.- VIII. Hypothalamus.- IX. Cerebellum.- X. Brain Stem.- XI. Spinal Cord.- XII. Retina.- References.- 22: Central Cholinergic Pathways: The Histochemical Evidence.- A. Introduction.- B. Techniques.- I. Immunohistochemistry for ChAT.- II. AChE Histochemistry.- III. Ancillary Techniques.- C. Central Cholinergic Systems.- I. Cholinergic Cell Groups.- II. Cholinergic Pathways.- D. Conclusions.- References.- 23: Central Cholinergic Transmission: The Physiological Evidence.- A. Introduction.- B. Nicotinic Synapses.- I. Characteristics of Peripheral Synapses.- II. Central Nicotinic Synapses.- C. Muscarinic Synapses.- I. General Considerations.- II. Forebrain Cholinergic System.- D. Conclusions.- References.- VII. Neuropathology of Cholinergic Transmission.- 24: The Cholinergic System in Aging.- A. The Process of Aging of Cholinergic Synapses: Hypotheses and Facts.- B. Aging of the Neuromuscular Junction.- I. Skeletal Muscle of Rodents.- II. Avian Iris NMJ.- C. ACh Synthesis and Metabolism in Brains of Aging Animals.- D. Cholinergic Receptors and Their Pharmacology.- E. Experimental Models of Dementia and Aging Based on Chemical Lesions of Cholinergic Systems.- F. Brain Transplants into ACh-Deficient Animals.- G. Cholinergic Deficits in Normal Aging and in Alzheimer’s Disease.- References.- 25: Disorders of Cholinergic Synapses in the Peripheral Nervous System.- A. Introduction.- B. Presynaptic Disorders of the Neuromuscular Junction.- I. Lambert-Eaton Myasthenic Syndrome.- II. Intoxication with Botulinum Toxin in Man.- III. Other Toxins Acting on Presynaptic Terminals.- IV. Congenital Myasthenia.- C. Postsynaptic Disorders of the Neuromuscular Junction.- I. Myasthenia Gravis (Acquired Autoimmune Myasthenia).- II. Congenital Myasthenia.- III. Inhibition of AChE.- IV. Snake Neurotoxins.- D. Disorders of the Peripheral Somatic Nervous System.- I. Neuropathies with Predominant Motor Fibre Dysfunction and Motoneuron Disorders.- II. Amyotrophic Lateral Sclerosis.- E. Autonomic Neuropathies.- I. Clinical Tests for Autonomic Involvement.- II. Cholinergic Autonomic Dysfunction in Diabetes Mellitus.- III. Acute Pandysautonomia.- IV. Animal Models of Autonomic Neuropathy.- V. Generalized Smooth Muscle Disease with Intestinal Pseudoobstruction.- F. Glossary.- References.- 26: Central Cholinergic Neuropathologies.- A. Introduction.- B. Pathological Processes.- I. Disposing Factors.- II. Metabolic.- III. Genetic.- IV. Neuronal Loss of Unknown Cause.- V. Environmental Poisons and Infective Agents.- C. Central Cholinergic Neuropathies.- I. Alzheimer’s Disease.- II. Down’s Syndrome.- III. Parkinson’s Disease.- IV. Huntington’s Chorea.- V. Motoneuron Disease.- D. Conclusion.- References.