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SelectiveNeurotoxicityContributors
K. Aktories, E.X. Albuquerque, H.G. BaumgartenC.-M. Becker, S. Becker, J.O. Dolly, P. GierschikH. Glossmann, R.D. Gordon, I. Hanin, H. HerkenH. Hortnagel, P. Holzer, F. Hucho, K.H. JakobsJ. Jarv, B.B. Johansson, I.J. Kopin, J. KrieglsteinS.C.R. Lummis, I.L. Martin, H. Meves, J. NuglischS. Ochs, Y. Olsson, J. Striessnig, K.L. SwansonV.I. Teichberg, H.H. Wellhoner, W.J. ZellerB. Zimmermann
Editors
Hans Herken and Ferdinand Hucho
\
Vyi
Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest
Contents
CHAPTER 1
Cellular and Subcellular Targets of Neurotoxins: The Conceptof Selective VulnerabilityH.G. BAUMGARTEN and B . ZIMMERMANN. With 12 Figures 1
A. Introduction 1B. Central Glutamatergic and Aspartatergic Pathways as Mediators
of Excitotoxicity 3C. Role of Active Transport Systems as Mediators of Selective
Neurotoxicity 7D. The Central Dopaminergic Systems as Targets of Neurotoxins . . . 8E. The Central Noradrenergic Systems as Targets of Neurotoxins . . . 9F. The Central Serotonergic Systems as Targets of Neurotoxins . . . . 11G. The Central Cholinergic Systems as Targets of Neurotoxins . . . . 14H. Cholinoceptive Mechanisms as Mediators of CNS Toxicity 16J. Vulnerability of the CNS to Antiniacin Compounds 18K. Vulnerability of the CNS to Drugs Affecting Oxidation-
Phosphorylation Coupling 20L. Vulnerability of Neurons Due to the Interaction of Toxins with
the Cytoskeleton 20References ' 22
C H A P T E R 2
Protective Barriers in the Peripheral Nervous Systemto Neurotoxic AgentsY. OLSSON. With 5 Figures 29
A. Toxic Injury and Protective Barriers of the Nervous System . . . . 29B. Microenvironment of Peripheral Nerves 29
I. Intrafascicular Structural Components 30II. Intrafascicular Fluid . 31
1. Composit ion 322. Formation and Resorption 323. Intrafascicular Flow 33
XII Contents
C. Barrier in the Vasa Nervorum of Peripheral Nerves 34I. Blood Supply 34
II. Vascular Permeability 351. Endoneurial Vessels 362. Epineurial Vessels 39
D. Barrier in the Perineurium of Peripheral Nerves 39I. Structure 40
II. Properties 411. Barrier to Various Compounds 422. Site of the Barrier 43
E. Barriers in Peripheral Ganglia 44I. Blood Supply 44
II. Vascular Permeability 44III. Extracellular Spaces 45IV. Capsule 46
F. Barriers and Toxic Lesions of the PNS 47I. Diphtheric Neuropathy 48
II. Neuropathies Due to Metal Intoxication 481. Lead Intoxication 482. Mercury Intoxication 493. Cadmium Intoxication 50
III. Neuropathy Due to Industrial Agents 511. Toxic Oil Syndrome . 51
IV. Neuropathy Due to Drugs 521. Hexachlorophene Neuropathy 522. Isoniazid Neuropathy • • • 533. Doxorubicin Neurotoxicity 534. Neurotoxicity of Local Anesthetics 54
G. Concluding Remarks 55References 56
CHAPTER 3
Protective Barriers in the Nervous System Against Neurotoxic Agents:The Blood-Brain BarrierB.B. JOHANSSON. With 2 Figures 67
A. Introduction 67B. Morphology of Brain Endothelial Cells 67C. Endothelial Cell Polarity 68D. Possible Role of Perivascular Astrocytes 68E. Passage Across the Endothelial Cell Membrane 69
I. Role of Lipid Solubility 691. Hexacarbons 692. Carbon Disulfide 69
Contents XIII
3. Organophosphorus Compounds 704. Methyl Mercury 705. Triethyltin 70
II. Transport Mechanisms 701. The Glucose Carrier 702. Carriers for Amino Acids 713. Peptides 714. The Monocarboxylic Acid Transporter 715. Organic Acids 726. Electrolytes 727. Others 72
F. Enzymatic Barriers 72G. Spontaneous and Induced Fluctuations of Blood-Brain Barrier
Function 73H. Methods to Facilitate Passage of Substances from Blood to Brain . . 74
I. Increasing Lipid Solubility 74II. Cationization and Glycosylation 75
III. Coupling to Substances Entering by Receptor-MediatedTransport 75
IV. Liposome Entrapment 75V. Methods to Open the Blood-Brain Barrier Experimentally . . 75
J. Long-Term Consequences of Blood-Brain Barrier Alterations . . . 76K. Substances that Enter the Brain by Primarily Damaging
the Blood-Brain Barrier 76L. Retrograde Intraaxonal Transport in Motor Nerves 76M. Areas Lacking a Blood-Brain Barrier 76N. Summary 77References 77
CHAPTER 4
Kinetic and Metabolic Disorders of Axoplasmic Transport Inducedby Neurotoxic AgentsS. OCHS. With 1 Figure 81
A. Introduction 81B. The Transport System 81
I. Characteristics of Anterograde Transport 81II. Retrograde Transport and Turnaround 83
III. Transport Models 841. The Fast Transport Mechanism 842. Slow Transport and the Unitary Hypothesis . 85
C. Neurotoxins 86I. Cell Body Actions 86
II. Generalized Actions on Fibers 87
XIV Contents
1. Agents Acting on the Axolemma 87a) Tetrodotoxin, Batrachotoxin 87b) Local Anesthetics 88
2. Metabolic Blockers 883. Calcium and Calmodulin Blocking Agents 894. Tubulin-Binding Agents 905. Microtubule "Stabilizing" Agents 916. Sulfhydryl Blockers 91
III. Localized Actions of Toxicants on Fibers 921. Proximal Axonopathies 92
a) (3,P'-Iminodipropionitrile 92b) Aluminum 93
2. Distal Axonopathies 94a) Acrylamide 94b) Hexacarbons 95c) p-Bromophenylacetylurea 96d) Zinc Pyridinethione 97e) Organophosphates 97f) Tulidora (Buckthorn) Toxin 98g) Alcohol 98
D. Conclusions 99References 100
CHAPTER 5
Metabolic Disorders as Consequences of Drug-Induced Energy DeficitsJ. KRIEGLSTEIN and J. NUGUSCH. With 10 Figures I l l
A. Introduction I l lB. Brain Energy Metabolism I l lC. Energy Deficits 113
I. Oxygen Deficiency 113II. Substrate Deficiency 114
D. Metabolic Disorders as Consequences of Energy Deficit 115I. Calcium Homeostasis 117
1. Routes of Ca2+Entry and Means of Ca2+Release 1172. Disturbances of Neuronal Calcium Homeostasis 1203. Calcium-Related Neuronal Damage 121
II. Oxygen Radicals 1211. Formation of Superoxide 122
a) Mitochondria . . : • 122b) Oxidative Enzymes 123c) Degradation of Arachidonic Acid
and Other Unsaturated Fatty Acids 123
Contents XV
d) Autoxidation 123e) Polymorphonuclear Leukocytes 124
2. Formation of Hydroxyl Radical 1243. Brain Damage and Free Radicals 125
E. Drug-Induced Energy Deficits 127I. Inhibitors of Oxidative Phosphorylation 127
1. Respiratory Chain Inhibitors 1272. ATP Synthetase Inhibitor 1293. Uncouplers 129
II. Ethanol 130III. Convulsives 131IV. Compounds Causing Energy Deficits by Enzyme/Membrane
Defects 132V. Ammonia 133
F. Concluding Remarks 133References 134
CHAPTER 6
Neurotoxic Synthesis by Enzymatic ErrorH. HERKEN. With 12 Figures 141
A. Introduction 141B. Lethal Synthesis 141
I. Toxicity of Fluoroacetic Acid 142II. Molecular Basis of Intoxication . .• 142
1. Synthesis of Fluorocitric Acid, Inhibitor of Aconitase . . . 144III. Citrate Accumulation — A Marker in Fluoroacetate
Intoxication 146C. Biosynthesis of Neurotoxic Dinucleotides 147
I. The NAD(P) Glycohydrolase-Transferase Exchange Reaction . 147II. 3-Acetylpyridine and 3-Acetylpyridine-Adenine-
Dinucleotides 1491. Neurotoxic Symptoms 1492. Molecular Basis of Intoxication 150
a) Synthesis of Nucleotides Containing 3-Acetylpyridinein the Brain 150
3. Distribution of 3-APADP in the Brain Region 1514. Dysfunction of Oxidoreductases with Nucleotides
Containing 3-Acetylpyridine as Coenzyme 1525. Predilection Sites of Functional Disorders and Lesions
in the Central Nervous System 1546. Metabolites of 3-Acetylpyridine 156
III. 6-Aminonicotinamide and 6-Aminonicotinamide-Adenine-Dinucleotides 157
XVI Contents
1. Neurotoxicity . . . 1572. Biochemical Basis of Action 158
a) Synthesis of Nucleotides Containing6-Aminonicotinamide by NAD(P) Glycohydrolase . . . 158
3. 6-ANADP, Inhibitor of Oxidoreductases, and the Blockadeof the Hexose Monophosphate Pathway 160
4. Inhibition of Phosphoglucose Isomeraseby Phosphogluconate 164
5. Carbohydrate Metabolism in the Brain After Inhibitionof Phosphoglucose Isomerase 165
6. Inhibition of Glucose Utilization in the Glutamatey-Aminobutyric Acid Route 169
D. Lesions of Neuroglia Cells 170E. 6-Aminonicotinamide Induces a Parkinson-Like Syndrome . . . . 172
I. Decrease of Tetrahydrobiopterin Content and Dopa Productionin PC12 Clonal Cell Line Induced by 6-Aminonicotinamide . . 175
II. De Novo Synthesis of Biopterin and the Salvage Pathwayof Synthesis 177
III. Biopterin Recycling Pathway and Dopa Production 179References 180
CHAPTER 7
Neurotropic CarcinogenesisW.J. ZELLER . . . . - . . . . ' 193
A. Introduction 193B. Neurotropic Carcinogenicity of Alkylnitrosoureas 194
I. Activity in Adult Animals 1941. Methylnitrosourea, Ethylnitrosourea 1942. Neurotropic, Carcinogenicity of Alkylnitrosoureas
with Increasing Length of the Alkyl Substituent 196II. Transplacental and Perinatal Activity of Alkylnitrosoureas . . 197
1. Transplacental Activity of Ethylnitrosourea in Rats . . . 197a) Comparative Sensitivity of the Nervous System
to Ethylnitrosourea in Different Phasesof Development: Interspecies Comparisons 197
2. Transplacental and Postnatal Activity of FurtherCompounds of the Homologous Seriesof Alkylnitrosoureas in Rats 203
III. Diagnosis and Histology of Neurogenic Tumorsin Rodents 203
IV. Neurotropic Carcinogenesis in Nonhuman Primates 206V. Further N-Nitroso Compounds 206
Contents XVII
VI. Azo-, Azoxy-, and Hydrazo compounds 207VII. Aryldialkyltriazenes 208
VIII. Other Alkylating Agents and Miscellaneous Compounds . . 210IX. Mechanisms Involved in Neurooncogenesis 211X. Malignant Transformation of Rat Neural Cells
In Vitro and In Vivo 215References 217
CHAPTER 8
Neurotoxic Phenylalkylamines and IndolealkylaminesH.G. BAUMGARTEN and B. ZIMMERMANN. With 10 Figures 225
A. Introduction 225B. Hydroxylated Analogues of Dopamine 226
I. False Transmitter Potential of 6-Hydroxydopamine , 226II. Structure-Activity Relationship of Dopamine Analogues . . . 227
1. Competition for Catecholamine and SerotoninTransport Sites 227
2. Acute Displacement of [3H]Norepinephrineby Hydroxylated Phenylethylamines 228
3. Acute and Long-Term Depletion of TissueNorepinephrine Content by Various Phenylethylamines . . 228
4. Long-Term Effects of Trihydroxyphenylethylamineson the Uptake of [3H]Norepinephrine In Vivo 229
5. Time Course of Effects of 6-Hydroxydopamineon (3H)Norepinephrine Uptake and on CNS CatecholamineLevels 229
III. Autoxidation and Catalyzed Oxidation of Dopamineand Trihydroxyphenylethylamines 2311. Pathways, Products, and Byproducts of Autoxidation . . . 2322. Radical-Catalyzed Oxidation 233
IV. Effect of Radical Scavengers on the Axodestructive Potencyof 6-Hydroxydopamine In Vivo 237
V. Role of Covalent Modification of Proteins Versus Roleof Free Radicals in Toxicity of 6-Hydroxydopamine 2381. Studies in Protein Model Systems 2382. In Vivo Studies 2393. Studies in Enzyme Systems 2394. Studies in Cell Culture Systems 241
C. DSP-4-Targets and Mechanism of Action 246D. Hydroxylated Analogues of Tryptamine and Serotonin 248
I. False Transmitter Potential of 5,6- and5,7-Dihydroxytryptamine 248
II. Structure-Activity Relationship 249
XVIII Contents
1. Competition for Monoamine Uptake Sites 2492. Impairment of [3H]-Serotonin and
[3H]-Norepinephrine Uptake 2513. Long-Term Effects of Dihydroxytryptamines on Cerebral
Monoamine Levels and Morphology of SerotonergicAxons 252
III. Autoxidation of Dihydroxytryptamines 2531. Pathways, Products, Byproducts, and Biological
Consequences of Autoxidation of 5,6-DHT 2552. Pathways, Products, Byproducts, and Biological
Consequences of Autoxidation of 5,7-DHT 259a) Keto-Enol Tautomerism 259b) Characteristics, Products, and Biological
Consequences 2593. Relevance of Autoxidation for Neurotoxicity 261
IV. Potential Intracellular Catalytic Mechanisms Involvedin Enhancement of Autoxidation of 5,7-DHTand Radical Formation 262
E. Substituted Amphetamines 265I. Neurotoxicity 265
II. Importance of Pharmacokinetics and Metabolismin the Long-Term Actions of Fenfluramine 267
III. Do Amphetamines Cause Acute Destruction of SerotonergicAxons like 5,7-DHT? 269
IV. Relevance of 6-Hydroxydopamine-and Dihydroxytryptamine-Induced Neurotoxicity 2701. Drug-Induced Toxicity in Central Monoaminergic
Neurons 2702. Monoamine Neurotoxins, Aging, and Disease 274
F. Conclusions 276References 279
CHAPTER 9
Toxins Affecting the Cholinergic SystemH. HORTNAGL and I. HANIN. With 2 Figures 293
A. Introduction 293B. Target Sites of Cholinergic Toxins at Various Levels
of the Cholinergic Neuron 294C. Toxins Effective at the Perikaryon of the Cholinergic Neuron . . . 296D. Toxins Effective at the Level of the Cholinergic Nerve Terminal . . 298
I. High-Affinity Choline Transport (HAChT) System 2981. Reversible Interactions 2982. Irreversible Interactions 300
Contents XIX
a) In Vitro Studies 300b) Effects in Neuronal Tissue Culture Systems 301c) In Vivo Studies 301d) Structural Requirements and Question of
Specificity of AF64A 304II. Acetylcholine Synthesis, Storage, and Release 306
1. Inhibition of Acetylcholine Synthesis 3062. Inhibition of Acetylcholine Storage 3073. Acetylcholine Release 308
III. Other Toxins at the Presynaptic Level 309E. Toxins Interfering at the Level of the Synapse 310F. Neurotoxins with Miscellaneous Actions, Preferentially Affecting
Cholinergic Pathways 313I. Colchicine 313
II. Ethanol 315III. Aluminum 316
G. Concluding Remarks 317References 318
CHAPTER 10
Mechanisms of l-Methyl-4-Phenyl-l,2,3,6-TetrahydropyridineInduced Destruction of Dopaminergic NeuronsI.J. KOPIN. With 1 Figure 333
A. Introduction 333B. Bioactivation of MPTP to MPP + by Monoamine Oxidase 334C. Toxicity of MPTP Analogues 335D. Alternative Routes for MPTP Metabolism 337.E. Mechanism of MPTP Activation by Monoamine Oxidase . . . . . 338
I. Inhibition of Monoamine Oxidase by MPTP 338II. Cellular Localization of Monoamine Oxidases 339
III. Uptake of MPP+ 341F. Molecular Bases for MPP+Toxicity 342
I. Inhibition of Mitochondrial Respiration by MPP+ 344G. Role of Neuromelanin in MPTP Toxicity 347H. Conclusion 348References 349
CHAPTER 11
Tetanus and Botulinum NeurotoxinsH.H. WELLHONER. With 1 Figure 357
A. Introduction 357B. Sources of Clostridial Neurotoxins 358
XX Contents
C. Production, Purification, and Structure 358I. Introduction 358
II. Terminology of the Toxin Fragments 359III. Production and Purification 360IV. Primary Structures 361
1. Tetanus Toxin 3612. Botulinum A Toxin 3623. Botulinum B Toxin 3634. Botulinum Cl Toxin 3635. Botulinum D Toxin 3636. Botulinum E Toxin 363
V. Higher Structures 3631. Crystallography 3632. Secondary Structure 3643. Tertiary Structure 364
VI. Binding, Uptake, Routing, and Action of ClostridialNeurotoxins as a Function of Their Subunits and Structure . . . 3651. Introduction • . 3652. Isotoxins and Subunits of the Clostridial Neurotoxins . . . 365
a) Nicking 365b) Function of the L-Chain 366c) Function of the H-Chain 366d) Functions Assigned to the C-Terminal Part
oftheH-Chain,Hc 367e) Functions Assigned to the N-Terminal Part
of the H-Chain 367f) Interaction of the L-Chain with the H-Chain, HN . . . . 367g) The L-Chain Linked to the C-Terminal Part
of the H-Chain, L-HN 3673. Modification of Amino Acids 368
D. Binding of Clostridial Neurotoxins to Cells and the Routingof the Toxins Through Neurons 370
I. The Three-Step Model 370II. Binding 371
1. Cell Specificity 3712. Affinity of Binding 3733. Chemical Nature of the Binding Sites 373
III. Uptake of Clostridial Neurotoxins into Endosomesof Neurons 376
IV. Handling of the Clostridial Neurotoxinsin the Endosomes 377
V. Axonal Transport 378VI. Elimination and Degradation 379
VII. Transsynaptic Transport 380
Contents XXI
E. Actions of Clostridial Neurotoxins 380I. Introduction 380
II. The Locus and the Phenomenology of Action 3811. Clostridial Neurotoxins do not Impair Conduction 3812. Ion Fluxes Through the Plasma Membranes
of Presynaptic Terminals 381a) Action on Calcium Fluxes Through Neuronal
Plasma Membranes 381b) Influence of Elevated Extracellular Ca2+ Concentration,
of Other Cations, and of Aminopyridines 3823. Actions on the Synthesis, Reuptake, Repartition,
and Storage of Transmitters 383a) Synthesis 383b) Uptake 383c) Content 383d) Compartmentalization 384
4. Clostridial Neurotoxins Impair the ReleaseofTransmitters,Neurohoromones,andNeuromodulators . . 384a) Biochemical and Biophysical Evidence 384b) Quantitative Comparisons . 389
5. Action on Postsynaptic Cells 3916. Late Effects 391
a) Damage to Neurons 391b) Sprouting 391c) Large-Sized Mepps 392
7. Action on Nonneuronal Cells 3928. Action on Multicellular Systems 392
a) Neuronal Systems 392b) Nonneuronal Systems 392
III. Intracellular Mode of Action 393G. Antibodies Against Clostridial Neurotoxins as Experimental Tools . 394
I. Monoclonal Antibodies 394II. Neutralization of Cell-Associated Clostridial
Neurotoxins with Antibodies 395References 396
CHAPTER 12
Capsaicin: Selective Toxicity for Thin Primary Sensory NeuronsP. HOLZER. With 1 Figure 419
A. Introduction 419B. Types and Targets of Action - . . . 420
I. Types of Primary Afferent Neurons 420II. Acute Exictatory Effects on Sensory Neurons 421
XXII Contents
1. Targets of Action 4212. Consequences of Excitation 424
III. Intermediate Effects on Sensory Neurons 4251. Sensitization and Desensitization 4252. Blockade of Nerve Conduction 426
IV. Neurotoxic Effects on Mammalian Sensory Neurons 4271. Effects of Systemic Treatment in Newborn Mammals . . . 427
a) Rat 427b) Other Mammals 432
2. Effects of Systemic Treatment in Adult Mammals 433a) Rat 433b) Guinea-Pig 436c) Other Mammals 437
3. Effects of Periaxonal Application 438a) Rat 438b) Other Mammals 439
4. Effects of Local Application 440a) Intrathecal or Intracisternal Administration 440b) Intracerebroventricular Administration 441c) Topical Administration to Specific Brain Regions . . . . 441d) Topical Administration to Peripheral Endings
of Sensory Neurons 4415. Effects on Sensory Neurons in Vitro 4426. Effects on Sensory Neurons in Culture 4437. Age, Strain, and Species Differences in Sensitivity 444
V. Acute and Long-Term Effects in Nonmammalian Species . . . 445VI. Summary 446
1. Capsaicin-Sensitive Neurons 4462. Neurons not Sensitive to Capsaicin 447
C. Mechanisms of Action . . . 448I. Structure-Activity Relationships 448
II. Effects on the Cell Membrane 4511. Sensory Neuron-Selective Effects 4512. Cell-Nonselective Effects 452
III. Intracellular Effects 4531. Ion Accumulation, Peptide Release,
and Biochemical Effects 4532. Nonspecific Desensitization 4543. Neurotoxicity 455
IV. Ruthenium Red as a Capsaicin Antagonist 456V. Interaction with Nerve Growth Factor 457
VI. Sites of Action on Sensory Neurons 457VII. Summary 458
D. Capsaicin as a Pharmacological Tool 459References 460
Contents XXIII
CHAPTER 13
Excitotoxins, Glutamate Receptors, and ExcitotoxicityV.I. TEICHBERG 483
A. Introduction 483B. Excitotoxins and Excitotoxicity 483C. Excitotoxins and Glutamate Receptors 483
I. The N-Methyl-D-Aspartate Receptor 4841. Pharmacological and Electrophysiological
Characterization 4842. Biochemical and Structural Characterization 486
II. The Kainate Receptor 4871. Pharmacological and Electrophysiological
Characterization 4872. Biochemical and Structural Characterization 489
III. The a-Amino-3-Hydroxy-5-Methyl-4-IsoxazolepropionateReceptor 4911. Pharmacological and Electrophysiological
Characterization 4912. Biochemical and Structural Characterization 491
IV. The 2-Amino-4-Phosphonobutyrate Receptor 492V. The rran5-l-Amino-l,3-Cyclopentanedicarboxylate Receptor . 492
1. Pharmacological and ElectrophysiologicalCharacterization 492
D. Mechanisms of Action of Excitotoxic Substances 493I. jV-Methyl-D-Aspartate-Induced Excitotoxicity 494
1. Early Events: Role of Sodium/Chloride Ions 4942. Late Events: Role of Calcium Ions and "Downstream
Processes" 495a) Perturbation of Cytoskeletal Organization 495b) Phospholipase Activation 496c) Endonuclease Activation 496d) Protein Kinase C Activation 496e) Xanthine Oxidase Activation 497
II. Kainate- and Quisqualate-Induced Excitotoxicity 497E. Endogenous Mechanisms of Protection from Excitotoxicity . . . . 498
I. Receptor Desensitization 499II. Cellular Uptake of Glutamate 499
III. Calcium Homeostasis 499IV. Built-in Mechanisms 499
F. Mechanisms Contributing to Excitotoxicity 500I. Role of Afferences 500
II. Cellular Metabolism 500G. Excitotoxicology: New Perspectives 500References 500
XXIV Contents
CHAPTER 14
Convulsants and Gamma-Aminobutyric Acid ReceptorsS.C.R. LUMMIS and I.L. MARTIN. With 8 Figures 507
A. Introduction 507B. Pharmacology and Structure of the GAB A A Receptor 508C. Competitive Antagonists at the GABAA Receptor 511D. Convulsant Agents Acting Through the Picrotoxin/Convulsant
Recognition Site 514E. Convulsant Agents Acting Through the Benzodiazepine
Recognition Site 522F. Conclusions 526References 527
CHAPTER 15
Convulsants Acting at the Inhibitory Glycine ReceptorC.-M; BECKER. With 6 Figures 539
A. The Glycinergic System of the Mammalian Central NervousSystem 539I. Postsynaptic Receptors 539
II. Glycine Receptors and Convulsants 540B. Toxicology: Strychnine as a Prototypic Glycine Receptor
Antagonist 540I. Symptoms of Strychnine Intoxication 540
II. Strychnine's Effect on Motor Regulation and theSomatosensory System 541
III. Audition and Vision 542IV. Other Central Nervous System Functions 543
C. The Inhibitory Glycine Receptor 545I. Receptor Structure and Isoforms 545
II. Ligand Binding Domains 548III. Interaction of Ligand Binding Domains 550IV. Ion Effects on Ligand Binding 552
D. Glycine Receptor Pharmacology 553I. Agonist Pharmacology of the Glycine Receptor 553
II. Strychnine, Derivatives, and Analogues 5551. Structure-Activity, Relationship of Strychnine-Like
Alkaloids 5552. Synthetic Fragments of Strychnine: (3-Spiropyr-
roldinoindolines 557III. Nonstrychnine Convulsants as Gylcine Receptor Ligands . . . 558
1. Synthetic Glycine Receptor Antagonists 5582. Alkaloid Antagonists and Opioids 558
IV. Nonselective GABAA Receptor Ligands 560
Contents XXV
1. Muscimol Analogues 5602. Ligands of the GABAA Receptor Modulatory Domain . . . 5623. AvermectinBia 5634. Convulsant Steroids 5635. Channel Blockers 564
V. Various Effects on Glycine Receptor Function 565E. Conclusions and Perspectives 565References 565
CHAPTER 16
Peptide Toxins Acting on the Nicotinic Acetylcholine ReceptorF. HUCHO. With 6 Figures 577
A. Introduction 577I. Toxins as Tools in Neurochemical Research 577
II. Toxins vs. Antibodies 578B. Scope 578C. The Biochemistry of the Acetylcholine Receptor 579
I. Assay and Isolation 579II. Structure 579
1. Primary and Quaternary Structures 5792. Posttranslational Modifications 5803. Secondary Structure 5824. Neuronal Acetylcholine Receptors and Brain
a-Bungarotoxin Binding Protein 583HI. Function 583
D. a-Neurotoxins from Snake Venoms 585I. General Properties and Classification 585
II. Primary Structure 588III. Tertiary Structure 589IV. Functional Domain 591V. Binding Domain on the Acetylcholine Receptor 593
1. Quaternary Structure 5932. Primary Structure 594
E. Other Peptide Neurotoxins 597F. Conclusions and Outlook 598References 598
CHAPTER 17
Nicotinic Acetylcholine Receptors and Low Molecular Weight ToxinsK.L. SWANSON and E.X. ALBUQUERQUE. With 15 Figures 611
A. Introduction 611B. Nicotinic Acetylcholine Receptor Ion Channel Macromolecules . . 612
XXVI Contents
C. Toxins Affecting the ACh Recognition Site for ChannelActivation 615
I. Sulfhydryl Modification of the ACh Target 615II. Agonists 618
III. Antagonists 624D. Allosteric Agonist Sites 627E. Allosteric Antagonist Toxin Binding Sites 628
I. Electrophysiological Characteristics of AllostericToxin Actions 6311. Open Channel Blockade: Agonist and Voltage
Dependence 6312. Closed Channel Blockade: Voltage Dependence
or Voltage and Time Dependence 6353. Desensitization: Agonist and Time Dependence 637
II. Antagonist Actions at Homologous Receptors 641III. Structure-Activity Relationships at Allosteric
Antagonist Sites 642F. Poisoning by Anticholinesterase Agents and Antidotal
Therapy Mediated by AChR Actions 644G. Conclusions 647References 648
CHAPTER 18Neurotoxic Agents Interacting with the MuscarinicAcetylcholine ReceptorJ. JARV. With 2 Figures 659
A. Introduction 659B. Toxicants Acting on the Muscarinic Receptor 660
I. Agonists and Antagonists 660II. Partial Agonists 661
III. Snake Venom Toxins 661C. Mechanism of Antagonist Interaction 662
I. Muscarinic Antagonists as Radioligands 662II. Kinetic Studies with Radioactive Antagonists 663
III. Kinetic Studies with Nonradioactive Ligands 665IV. Subtypes of Muscarinic Antagonists 667
D. Mechanism of Agonist Interaction 668I. Agonist-Antagonist Competition Studies 668
II. Binding Studies with Radioactive Agonists 669III. Kinetic Studies on Agonist-Antagonist Competition 670
E. Structure of Muscarinic Neurotoxic Agents 670I. Agonists and Antagonists: Qualitative Aspects 670
II. Agonists and Antagonists: Quantitative Aspects 673
Contents XXVII
F. Two-Site Model of the Muscarinic Receptor 675G. Conclusions 676References 676
CHAPTER 19
Peptide Toxins that Alter Neurotransmitter ReleaseJ.O. DOLLY. With 10 Figures 681
A. Introduction 681B. Toxins that Facilitate Indirectly the Neuronal Release
of Transmitters by Blocking K+ Channels . . 684I. Dendrotoxins 684
1. Effects in the Peripheral Nervous System 6842. Actions of a-Dendrotoxin and Its Homologues in the
Central Nervous System 686a) Neurophysiological Demonstration of Toxin-Induced
Increased Neuronal Excitability, Facilitated Releaseof Transmitters and Blockade of an IA-like K+ Current . . 686
b) Dendrotoxins Elicit Resting Efflux of Transmittersfrom Synaptosomes and Elevate Cytosolic Ca2+
Concentration 687II. Noxiustoxin and Charybdotoxin 689
C. Polypeptide Toxins with Multiple Effects on the NeuronalRelease of Transmitters 691I. P-Bungarotoxin and Related Phospholipase A2-Containing
Toxins . . . 6911. General Properties of p-Bungarotoxin, Notexin,
Crotoxin, andTaipoxin 6912. Triphasic Effects of Phospholipase A2Toxins on
Acetylcholine Release: Importance of the Blockadeof a Presynaptic K+Current 691
3. Insights into the Action of P-Bungarotoxin Gained fromStudies on Central Neuronal Preparations 693a) Electrophysiological Recordings in Brain Slices
Showing that p-Bungarotoxin Preferentially BlocksTransmitter Release . 693
b) Biochemical Evidence for Acceptor BindingUnderlying the Preferential Action of p-Bungarotoxinon Nerve Terminals 694
II. a-Latrotoxin 695D. Botulinum Neurotoxins and Tetanus Toxin: Unique Probes
for Studying Neurotransmitter Release 696I. Clostridial Proteins that Block Ca2+-Dependent Secretion
by Analogous Multi-Step Mechanisms 696
XXVIII Contents
1. Structural Features Common to Botulinum Neurotoxinsand Tetanus Toxin 697
2. Experimental Support for Triphasic Mechanismsof Toxin Action 697
3. Subtile Differences in the Pharmacological Effectsof Botulinum Neurotoxin Types A and B 699
II. Conclusive Evidence that Botulinum Neurotoxins ActIntracellularly to Block CA2+-Dependent Release ofTransmitters from Various Neurons and Exocrine Cells . . . . 699
III. Light Chain of Botulinum Neurotoxin BlocksCa2+-Dependent Secretion when Applied Inside MotorNerve Endings and Other Mammalian Cells: A VestigialIntracellular Role for Its Heavy Chain 701
IV. Optimal Targetting/Internalisation of Botulinum Neurotoxinat Mammalian Nerve Terminals Requires the IntactDi-Chain Form: Functional Domains in the Heavy Chain . . . 703
V. Activities of Hybrid Mixtures of the Chains of BotulinumNeurotoxins and Tetanus Toxin: Binding Via the HeavyChain to Distinct Ecto-Acceptors Underlies theirNeuronal Specificities 704
VI. Clues to the Molecular Basis of the IntracellularAction of Botulinum Neurotoxin 706
References 710
CHAPTER 20
Sodium Channel Specific Neurotoxins: Recent Advancesin the Understanding of Their Molecular MechanismS.BECKER and R . D . G O R D O N . With 2 Figures 719
A. Introduction 719B. Current Status of the Molecular Structure of the Sodium
Channel 719C. Description of Toxins by Class 723
I. Toxins that Inhibit Sodium Transport 7231. Heterocyclic Guanidines 7232. u-Conotoxins 724
II. Lipid-Soluble Toxic Activators of the Sodium Channel . . . . 7271. Batrachotoxin 727
III. North African a-Scorpion and Sea Anemone Toxins 7281. a-Scorpion Toxins 7282. Sea Anemone Toxins 730
IV. American P-Scorpion Toxins 731V. Other Toxins 732
Contents XXIX
1. Ciguatoxin 7322. Brevetoxin 733
D. Conclusions 733References 733
CHAPTER 21Potassium Channel ToxinsH. MEVES. With 6 Figures , . . . 739
A. Introduction 739B. Chemistry 739C. Binding Studies 741D. Cross-Linking Experiments 748E. Solubilized and Purified Binding Protein 748F. Electrophysiological Experiments 751
I. Apamin 751II. Charybdotoxin, Leiurotoxin, and Iberiotoxin 753
III. Noxiustoxin and Other Scorpion Toxins 756IV. Dendrotoxin, Mast Cell Degranulating Peptide,
P-Bungarotoxin 757V. Other Toxins 761
G. The Presumed Site of Action 761References 765
CHAPTER 22
Calcium Channel ToxinsJ. STRIESSNIG and H. GLOSSMANN. With 1 Figure 775
A. Introduction 775B. Calcium Channel Toxins from Venomous Snails: (o-Conotoxins. . . 776
I. co-Conotoxin GVIA is a Selective Blocker of N-Type,Dihydropyridine-Insensitive Calcium Channels 779
II. w-Conotoxin GVIA Reveals Functional AssociationsBetween Excitatory Amino Acid Receptors and NeuronalCalcium Channels 788
III. Probing the Structure and Location of N-Type CalciumChannels with co-Conotoxin GVIA Derivatives 790
C. Calcium Channel Toxins from Spider Venoms 792I. Peptide Toxins 792
1. co-Agatoxins . 7922. Hololena curta Toxins 7933. Plectreurys tristes Toxins 7944. AgelenaopulentaToxins 794
XXX Contents
II. Nonpeptide Toxins 794D. Calcium Channel Toxins from Snake Venoms: Taicatoxin 795E. Toxins with Claimed but Unproven Action on Calcium Channels . . 796
I. Maitotoxin 796II. Leptinotoxin-h 796
III. Goniopora Toxin 796IV. Apamin 797V. Atrotoxin 797
F. Future Prospects 797References 799
CHAPTER 23
ADP-Ribosylation of Signal-Transducing Guanine NucleotideBinding Proteins by Cholera and Pertussis ToxinP. GIERSCHIK and K.H. JAKOBS. With 2 Figures 807
A. Introduction 807B. Structure-Function Relationships of Cholera
and Pertussis Toxins 809I. Cholera Toxin 809
II. Pertussis Toxin 810C. Structure and Function of ADP-Ribosylation Factors 813D. Molecular Mechanisms of G-Protein ADP-Ribosylation
by Cholera and Pertussis Toxins 816I. Cholera Toxin 816
1. ADP-Ribosylation of Gs 8162. ADP-Ribosylation of Retinal Transducin 8173. ADP-Ribosylation of Gi/Go-Like G Proteins 818
II. Pertussis Toxin 8201. ADP-Ribosylation of Retinal Transducin 8202. ADP-Ribosylation of Gj/Go-Like G Proteins 821
E. Functional Consequences of G-Protein ADP-Ribosylationby Cholera and Pertussis Toxins 824
I. ADP-Ribosylation of Gs by Cholera Toxin 8241. Short-Term Effects 8242. Long-Term Effects 825
II. ADP-Ribosylation of G Proteins Other than Gs
by Cholera Toxin 826III. G-Proteins ADP-Ribosylation by Pertussis Toxin 828
F. Future Perspectives 830References 830
Contents XXXI
CHAPTER 24
Clostridium botulinum C2 Toxin and C. botulinumC3 ADP-RibosyltransferaseK. AKTORIES. With 1 Figure 841
A. Introduction . . 841B. Clostridium botulinum C2 Toxin 841
I. Origin and Structure 841II. The Binding Component 842
III. The Enzyme Component 842IV. Functional Consequences of the ADP-Ribosylation of Actin . 842V. Cytopathic Effects • 843
VI. Pharmacological Actions 843VII. Other Actin-ADP-Ribosylating Toxins 845
C. Clostridium botulinum C3 ADP-Ribosyltransferase 846I. Origin and Structure 846
II. Enzyme Activity 846III. Substrates 847IV. ADP-Ribosylation of Asparagine 848V. Functional Consequences 848
D. Concluding Remarks 849References 849
Subject Index 855
