Neuromuscular Junction

Has the neuromuscular junction been over-exposed or is it perhaps already a closed book? I asked myself this at a recent International Congress when an American colleague complained that the Journal of Physiology had articles on nothing but the neuromuscular junction, while another colleague asked why I was editing a volume on a subject about which everything was already known. It is worrying to think that these views may be shared by other people. I hope that this volume will convince my two colleagues and other readers that the neuromuscular junction is very much alive and continues to attract the interest of many workers from a variety of fields; strange as it may seem, the synapse between a motor nerve ending and muscle fibre, with its relatively simple architecture, is one of the most inter­ esting sites in the body-I do hope we have done it justice. The various chapters of this volume present a cross section of knowledge as viewed by a group of 13 individuals, actively engaged in research. Multi-author volumes such as this are frequently criticised on the grounds that chapters or sec­ tions overlap. I believe that such criticium is only valid where the overlap is repetitious. Where it results in the reader having available discussions of material from differing stand-points, overlap becomes a valuable feature of this type of publication.

Introductory Chapter The Neuromuscular Junction: Areas of Uncertainty.- Neuromuscular Block by Prolonged Depolarisation.- Desensitisation.- The Clinical Picture.- The Presence of Other Drugs.- The Importance of the Drug Structure and that of the Acetylcholine Receptor.- Pre-Synaptic or Post-Synaptic Action?.- Closing Remarks.- References.- 1 The Anatomy and Pathology of the Neuromuscular Junction.- A. Introduction.- B. Normal Muscle.- I. The Motor Unit.- II. Pattern of Innervation and Distribution of Motor End-Plates.- III. The Structure of the Neuromuscular Junction.- 1. Axon Terminals.- 2. Experimental Modifications of the Structure of the Axon Terminal.- 3. Transmitter Release and Synaptic Vesicles.- 4. The Postsynaptic Region.- 5. The Localization of Cholinesterase.- 6. The Basement Membrane.- 7. The Localization of Acetylcholine Receptors.- C. Development, Growth, and Plasticity of the Neuromuscular Junction.- 1. Development of the Neuromuscular Junction.- 2. Development in Tissue Culture.- 3. Structural Denervation.- D. The Neuromuscular Junction in Disorders of Transmission.- 1. Myasthenia Gravis.- 2. The Myasthenic Syndrome.- 3. Hereditary Motor End-Plate Disease in the Mouse.- 4. The Effects of Botulinum Toxin.- 5. The Effects of Tetanus Toxin.- E. The Neuromuscular Junction in Disorders of the Muscle Fibre.- F. Conclusion.- References.- 2 Neurochemistry of Cholinergic Terminals.- A. Introduction.- B. Methods for Extracting and Measuring Acetylcholine.- 1. Preparation of Tissues for Extraction of ACh.- 2. Extraction of ACh.- 3. Assay of ACh.- C. Acetylcholine Synthesis.- 1. Choline Acetyltransferase: its Location and Physical Properties.- 2. Choline Acetyltransferase: its Chemistry, Substrates, and Inhibitors.- 3. Choline Acetyltransferase: its Kinetics.- 4. Supply of Acetyl Groups for ACh Synthesis.- 5. Supply of Choline for ACh Synthesis.- 6. Transport of Choline.- 7. Inhibitors of Choline Transport.- 8. ACh Uptake.- 9. Control of ACh Synthesis.- D. Acetylcholine Storage.- 1. Brain.- 2. Ganglion.- 3. Skeletal Muscle.- 4. Electric Organ.- 5. Other Tissues.- E. Acetylcholine Release.- 1. Correlation of Neurochemical and Electrophysiological Data.- 2. ACh Content: Vesicles vs. Quanta.- 3. Is ACh Released from the Nerve-Terminal Cytoplasm?.- 4. Is Release of ACh Regenerative?.- 5. Calcium and ACh Release.- 6. Neurotoxins and ACh Release.- 7. Drugs and ACh Release.- 8. Cyclic Nucleotides, Prostaglandins and ACh Release.- 9. Contractile Proteins, Microtubules and Microfilaments.- 10. Are Quanta Released by Exocytosis?.- F. Acetylcholine Turnover.- 1. Tissue ACh Turnover during Rest and Activity.- 2. Preferential Release of Newly Synthesized ACh.- 3. ACh Turnover in Relation to Changes in Ultrastructure.- 4. ACh Turnover as Studied by Cell Fractionation Techniques.- 5. Transfer of ACh between Pools or Compartments.- 6. A Tentative Model for ACh Storage and Metabolism.- G. Removal of Acetylcholine.- 1. Enzymatic Destruction.- 2. ACh Uptake.- 3. Diffusion from the Synaptic Cleft.- H. Axonal Transport of Materials Related to Cholinergic Transmission.- 1. Acetylcholinesterase.- 2. Choline Acetyltransferase.- 3. Acetylcholine.- 4. Other Materials.- 5. Effects of Agents that Block Axonal Transport.- 6. A Note on Other Trophic Influences Mediated by Cholinergic Nerves.- I. Prolonged Neurochemical Changes Resulting from Synaptic Activity.- 1. Causes of Synaptic Plasticity.- 2. Post-Tetanic Potentiation.- 3. Enzyme Induction.- 4. Possible Contribution by Glial Elements.- References.- 3 Transmission of Impulses from Nerve to Muscle.- A. Introduction.- B. The Muscle Fibre and the Action of Acetylcholine.- I. Some Relevant Properties of Muscle Fibres.- 1. The Membrane Potential and its Measurement.- 2. Factors Influencing the Membrane Potential.- II. The End-Plate Potential.- 1. Introduction.- 2. General Characteristics of the Permeability Change Caused by the Transmitter.- 3. The Representation of Transmitter Action in Electrical Terms.- 4. The Influence of the Non-Synaptic Membrane on the Response to Acetylcholine.- III. The Ion Selectivity of the Permeability Change Produced by the Transmitter.- 1. The Voltage Clamp Technique.- 2. The End-Plate Current.- 3. Relative Contribution of Different Ions to the Conductance Increase.- 4. Characteristics of the Additional Ion Channels.- 5. Evidence on Ion Selectivity from the Use of Radio-Isotopes.- IV. Localization of Acetylcholine Receptors.- 1. Introduction.- 2. The Ionophoretic Method of Drug Application.- 3. Evidence on Receptor Distribution from Ionophoretic Experiments.- 4. Other Electrophysiological Evidence on the Distribution of Receptors.- 5. Evidence on Receptor Distribution from Experiments with Labelled Antagonists.- 6. Denervated Muscle.- 7. Characteristics of Acetylcholine Receptors in Denervated Muscle.- V. The Interaction between Acetylcholine and its Receptors.- 1. Classical Models of Receptor Action.- 2. The “Allosteric” Model of the Receptor.- 3. New Evidence on Receptor Action: Acetylcholine “Noise”.- 4. The Response to Prolonged Application of Depolarizing Agents.- VI. Modification of Transmitter Action.- 1. Competitive Antagonism.- 2. Evidence for Competition between Curare Alkaloids and Acetylcholine.- 3. Other Agents which Influence Transmitter Action.- C. Pre-Synaptic Events.- I. Introduction.- II. Miniature End-Plate Potentials.- 1. Occurrence.- 2. Amplitudes of Miniature End-Plate Potentials.- 3. Abnormal Miniature End-Plate Potentials.- 4. The Rate of Spontaneous Release.- 5. External Recording of Spontaneous Discharge.- III. Evidence for the Quantal Nature of Evoked Transmitter Release.- 1. Intracellular Recording: Counts of “Failures”.- 2. Evidence from Extracellular Recording: Counts of Quanta.- 3. Amplitude Distribution of Responses.- 4. Variance of the Amplitude Distribution.- 5. Evidence that Fluctuations in Transmitter Release Reflect Variations in the Number of Quanta Released Rather than in the Amount of Transmitter per Quantum during Facilitation and Depression.- 6. Quantal Nature of Transmitter Release Evoked by Presynaptic Depolarization without Action Potentials.- IV. Physical and Statistical Models for Quantal Release.- V. The Calcium Hypothesis.- VI. Estimating Values of the Quantal Content.- 1. Methods.- 2. Estimates of Normal Quantal Contents.- 3. Errors in Quantal Content Estimates in the Presence of Drugs.- VII. Studies on Evoked Release of Transmitter.- 1. Methods of Evoking Release.- 2. Relationship between the Various Methods of Evoking Release.- VIII. Factors Affecting Evoked Transmitter Release.- 1. Calcium and Magnesium.- 2. Non-Specific Factors Affecting Evoked Release.- 3. Agents which Increase Evoked Transmitter Release.- 4. Substances which Reduce Evoked Transmitter Release.- 5. Relationship between Changes in Evoked and Spontaneous Release of Transmitter.- IX. Facilitation and Depression.- 1. Depression and Depletion of Evoked Transmitter Release.- 2. Short Term Facilitation.- 3. Post-Tetanic Potentiation (Presynaptic).- D. Postscript.- References.- 4A Depolarising Neuromuscular Blocking Drugs.- A. General Introduction.- B. An Introduction to the Pharmacological Actions of Decamethonium at the Neuromuscular Junction.- C. End-Plate Depolarisation by Decamethonium and Suxamethonium in vivo.- D. Effect of Decamethonium, Suxamethonium and Acetylcholine on the Electrical Properties of Single Mammalian Muscle Cells.- 1. Membrane Potential.- 2. Input Resistance.- 3. Effect of Acetylcholine on Membrane Potential.- 4. The Effect of Decamethonium in Chloride-Free Solution.- 5. The Effect of Ouabain.- E. Depolarisation Versus Desensitisation.- F. Species Differences and Depolarising Neuromuscular Blocking Drugs.- I. Man and Cat.- II. Other Mammalian Species.- III. Avian Muscle.- G. Factors which May Modify the Action of Depolarising Neuromuscular Blocking Drugs and Variations Due to Experimental Conditions.- I. The Effect of Lowered Muscle Temperature.- II. Tachyphylaxis.- III. “Potentiation” of a Maximal Twitch.- IV. Frequency of Stimulation.- H. Concluding Remarks.- References.- 4B Competitive Neuromuscular Blocking Drugs.- A. Introduction and Terminology.- B. Chemical Structure.- C. Methods Used to Measure Neuromuscular Blockade.- I. Muscle Contractions Evoked by Stimulation of the Motor Nerve.- II. Recording of Muscle Contraction.- 1. Selection of Strain Gauge.- 2. Optimal Muscle Length.- 3. Influence of Temperature.- 4. Correlation between Twitch Size and Receptor Occlusion.- III. Recording of Action Potentials.- IV. Measurements of Membrane Potential.- 1. Extracellular Recording.- 2. Intracellular Microelectrode Recording.- D. Distribution of Competitive Neuromuscular Blocking Drugs.- I. General Properties.- II. Transport of Neuromuscular Blocking Drugs across Cell Membranes.- 1. Entry into Liver Cell and Biotransformation.- 2. Excretion into Bile.- 3. Entry into Muscle Cells.- III. Plasma Protein Binding.- E. Factors Affecting Duration of Action in Animals and Man.- I. Species Variation.- 1. Potency.- 2. Duration of Action.- II. Biotransformation in the Liver.- III. Renal and Biliary Excretion.- IV. Redistribution.- 1. Binding in Extracellular Compartment.- 2. Binding at End-Plate Region.- V. Termination of Action by Chemical Inactivation of the Drug.- F. Mechanism of Action at Neuromuscular Junction.- I. Evidence for Competitive Antagonism in vitro.- II. Evidence for Competitive Antagonism in vivo.- 1. Quantitative Studies.- 2. Qualitative Studies.- III. Factors Affecting Neuromuscular Blocking Action.- 1. Sensitivity of Fast and Slow Fibres.- 2. Effect of Temperature.- 3. Effect of Age.- 4. Effect of Acidosis.- G. Effects at Cholinergic Synapses in the Autonomic Nervous System.- I. Actions on Autonomic Ganglia.- II. Actions on the Heart.- H. Histamine Release in Animals and Man.- J. Miscellaneous Drugs which Cause Muscle Paralysis.- I. General Anaesthetics.- II. Barbiturate and Non-Barbiturate Hypnotic Drugs.- III. Local Anaesthetics.- IV. Antibiotics.- References.- 4C Pharmacology of Anticholinesterase Drugs.- A. Introduction.- B. Morphology and Function of Acetylcholinesterase (AChE).- I. Localization of AChE at the Motor End-Plate.- II. Hydrolysis of ACh.- C. Inhibition of AChE.- I. Kinetics of Inhibition of AChE.- II. Measurements of the in vivo Inhibition of AChE.- D. Actions of Anticholinesterases of the Carbamate and Organophosphate Type and of Anilinium Ions.- I. Twitch Potentiation.- II. Fasciculations.- III. Tetanic Fade.- IV. Anticurare Action.- 1. Anticurare Action at Frequencies of Nerve Stimulation which Normally Produce Twitch Responses.- 2. Anticurare Action at Frequencies of Nerve Stimulation which Normally Produce a Sustained Contraction of Muscles.- V. Reversal of the Symptoms of Myasthenia Gravis.- VI. Selectivity of Action.- VII. Adaptation to Prolonged Inhibition of AChE.- VIII. Antidotal Effects of Tubocurarine and Reactivators of Phosphorylated AChE; Selectivity of Action of Reactivators.- IX. Inhibition of Cholinesterase (ChE).- General Conclusions.- Appendix I Studies on Frog Muscles.- Appendix II Anticholinesterases and Anilinium Ions Referred to in the Text.- Appendix III An Outline of the Methods Used to Calculate the Quantal Content of the e.p.p. and the Rate of Refilling and Size of the ACh Store in Nerve Terminals.- References.- 5A The Clinician Looks at Neuromuscular Blocking Drugs.- A. Introduction.- B. General Anaesthesia before Neuromuscular Blocking Drugs.- C. Clinical Influence of Neuromuscular Blocking Drugs.- D. Three Possibly Fatal Reactions to Suxamethonium.- E. Less Serious Reactions to Suxamethonium.- F. Personal Technique.- G. Conclusions.- References.- 5B Neuromuscular Blocking Drugs in Man.- A. Introduction.- B. Measurement of Drug Action.- I. Voluntary Muscle Contractions.- II. Direct Measurement of Neuromuscular Transmission in Man.- 1. General Aspects.- 2. Electrical Stimulation of Motor Nerves and Stimulus Schedules.- 3. Electromyographic Recording.- 4. Recording of Muscle Contractions.- 5. Experimental Conditions.- 6. Definition of Terms.- III. Quantitation of Neuromuscular Blockade and Assessment of Residual Blockade.- C. Pharmacokinetics of Neuromuscular Blocking Drugs.- I. Distribution and Elimination.- II. Plasma Protein Binding.- III. The Placental and Blood-Brain Barriers.- D. Action of Neuromuscular Blocking Drugs at the Neuromuscular Junction.- I. General Characteristics.- II. Influence of Anaesthetics.- III. Muscle Temperature and Blood Flow.- IV. Carbon Dioxide and Plasma pH.- V. Dual Block.- VI. Responses of Newborn Infants.- VII. Antibiotic Administration.- VIII. Suxamethonium and Muscle Pain.- IX. Suxamethonium and Plasma Cholinesterase.- X. Myopathy.- E. Other Actions of Neuromuscular Blocking Drugs.- I. Histamine Release.- II. Cardiovascular Actions.- III. Suxamethonium and Hyperkalaemia.- IV. Ocular Actions.- References.- 5C Twenty Years’ Experience with Decamethonium.- A. Introduction.- B. First Clinical Reports.- C. Analysis of 32000 Administrations of Decamethonium.- I. Surgical Experience.- II. Analysis.- III. Methods of Administration.- 1. Early Techniques.- 2. Present Techniques.- IV. Complications.- V. Cardiovascular System and Decamethonium.- VI. Muscle Pains and Decamethonium.- D. Assessment.- References.- Author Index.