Pharmacology of Neurotransmitter Release (eBook)

Preface 5
References 7
Contents 8
Contributors 10
Neurotransmitter Release 14
1 Principles of Neurotransmitter Release 15
2 Very Short History of the Analysis of Neurotransmitter Release 18
3 Basic Mechanisms of Release by Exocytosis 20
3.1 Rab-Proteins and Rab-Effectors 21
3.2 SNARE Proteins 21
3.3 SM Proteins 24
3.4 Mechanism of SNARE and SM Protein Catalyzed Fusion 24
4 Mechanism of Ca2+-Triggering: Ca2+-Channels, Ca2+- Buffering, and Synaptotagmin 25
4.1 Ca2+- Dynamics 25
4.2 Synaptotagmins as Ca2+- Sensors for Fast Neurotransmitter Release 26
5 Regulation of Release Beyond Ca2+-Triggering 29
5.1 Acetylcholine-Receptor-Mediated Ca2+- Influx into Presynaptic Nerve Terminals 29
5.2 Ca2+- Channel Modulation by Presynaptic Receptors 30
5.3 Presynaptic Long-Term Plasticity Mediated by cAMP- Dependent Protein Kinase A ( PKA) 30
6 Ca2+-Induced Exocytosis of Small Dense-Core Vesicles and LDCVs 31
7 Presynaptic Drug Targets 32
References 32
Pharmacology of Neurotransmitter Release: Measuring Exocytosis 35
1 Electrophysiological Detection of Secretion 1.1 Electrical Detection of Neurotransmitter Release Using Postsynaptic Ionotropic Receptors 36
1.2 Detection of Probability of Neurotransmitter Release 38
1.3 Studying Synaptic Vesicle Recycling Using Electrophysiological Techniques 40
1.4 Detection of Neurotransmitter Secretion Through Amperometric Recordings 41
1.5 Detection of Membrane Fusion via Presynaptic Capacitance Measurements 42
2 Fluorescent Visualization of Synaptic Vesicle Fusion and Recycling 2.1 Optical Detection of Neurotransmitter Release 43
2.2 Functional Analysis of Exocytosis and Vesicle Recycling Using Styryl Dyes 44
2.3 Detection of Synaptic Vesicle Exocytosis and Endocytosis Using pHluorin- Tagged Synaptic Vesicle Proteins 48
2.4 Comparison of Styryl Dye Imaging and pHluorin-Based Visualization of Exo- Endocytosis 49
3 Biochemical Approaches to Measuring Neurotransmitter Release 50
References 52
Presynaptic Calcium Channels: Structure, Regulators, and Blockers 56
1 Subtypes and Physiological Functions of Calcium Channels 57
2 Molecular Structure of Voltage-Gated Calcium Channels 60
3 Consequences of Calcium Channel Gene Knockout 62
4 Calcium Channelopathies Involving P/Q-Type Calcium Channel a1 Subunits 64
5 Calcium Channel Pharmacology 5.1 Peptide Blockers 65
5.2 Small Organic Compounds Blocking N-type Channels 66
6 Regulation by G Protein–Coupled Receptors 67
7 Regulation of Calcium Channels by Synaptic Proteins 70
8 Regulation of Presynaptic Calcium Channel Activity by Protein Kinases 72
9 Feedback Regulation by Calcium Binding Proteins 73
10 Summary 75
References 75
Pharmacology of Neurotransmitter Transport into Secretory Vesicles 87
1 Introduction: Neurotransmitter Recycling 88
2 H+ Electrochemical Gradient 2.1 Vacuolar H+- ATPase 90
2.2 Chloride Channels 92
2.3 Ionophores 92
3 Vesicular Transport Proteins 3.1 Vesicular Monoamine Transporters (VMAT1 and VMAT2) 93
3.2 Vesicular Acetylcholine Transporter (VAChT) 99
3.3 Vesicular GABA and Glycine Transporter (VGAT) 101
3.4 Vesicular Glutamate Transporters (VGLUT1-3) 102
3.5 Other Transporters on Vesicles 106
4 Conclusions 107
References 108
Core Proteins of the Secretory Machinery 117
1 SNAREs 118
1.1 Structure of the Neuronal SNAREs 119
Qa Qb Qc R 120
Syntaxin 1A SNAP-25 120
Synaptobrevin 2 120
Neuronal SNARE-core complex 120
1.2 Assembly and Disassembly of SNAREs: Mechanistic Considerations 122
2 Sec1/Munc18 (SM) Proteins 125
2.1 SM Protein Interactions with SNAREs 126
2.2 Munc18-1–an Oddity among the SM Proteins? 126
3 Synaptotagmins 3.1 Synaptotagmin Family 127
3.2 Synaptotagmin 1 as Ca2+- Sensor for Fast Neurotransmitter Release 128
3.3 Molecular Mechanism of Synaptotagmin 1 129
4 Rab Proteins 129
4.1 Rab3 130
4.2 Rab3 Effectors 131
5 Endocytic Proteins 131
5.1 Kiss-and-Run Exocytosis/Endocytosis 132
5.2 Clathrin-Mediated Endocytosis (CME) 133
5.3 Coupling Exocytosis to Endocytosis 135
References 135
Presynaptic Neurotoxins with Enzymatic Activities 138
1 Introduction 139
2 Toxicity of BoNTs and of SPANs 140
3 The Diseases 3.1 Tetanus 141
3.2 Botulism 142
3.3 Features of Envenoming from Bites of Snakes Producing Venoms Containing Large Amounts of PLA2 Presynaptic Neurotoxins 143
4 Structural Organization of Tetanus and Botulinum Neurotoxins 144
4.1 The Binding Domain 146
4.2 The Translocation Domain 146
4.3 The Catalytic Domain 148
5 Structure of the Snake Presynaptic PLA2 Neurotoxins 148
6 The Mode of Action of Clostridial Neurotoxins 149
6.1 Binding 150
6.2 Internalization 152
6.3 Membrane Translocation 152
6.4 SNARE Proteins’ Specific Metalloproteolytic Activity 153
7 The Mode of Action of PLA2 Snake Presynaptic Neurotoxins 155
8 Regeneration of the Skeletal Neuromuscular Junction and the Innervated Muscle Fibers after Poisoning by Botulinum or Snake Neurotoxins 161
9 Clostridial Neurotoxins in Cell Biology 163
10 Therapeutic Uses 164
References 165
a-Latrotoxin and Its Receptors 180
1 a-LTX and Release of Neurotransmitters 181
1.1 Target Cells 182
1.2 Site and Mode of Action 182
1.3 Ca2+- Independent Release 183
1.4 Ca2+- Dependent Release 183
2 The Structure of a-LTX 184
2.1 Sequence Analysis 184
2.2 Higher-Order Structures 184
2.3 Recombinant a-LTX 187
3 Membrane Pore 188
3.1 Tetramerization 188
3.2 Receptor Interaction 188
3.3 Membrane Insertion 189
3.4 Features of the Pore 190
3.5 Can the Pore Explain Everything? 194
4 Receptors 195
4.1 Neurexin 195
4.2 Latrophilin 198
4.3 Protein Tyrosine Phosphatase s 202
4.4 a- LTX Receptors and Signaling 204
5 Overview of Mechanisms 207
References 208
Presynaptic Signaling by Heterotrimeric G- Proteins 216
1 Overview of G Protein Signaling 217
1.1 Types of G-Protein 218
1.2 Receptor Coupling and Selectivity 220
1.3 G-Protein–Effector Coupling 220
1.4 Rates of G-Protein–Mediated Events 221
1.5 Further Notes on RGS Proteins 222
2 G-Proteins and Transmitter Release 224
2.1 Effects on Ca2+ Entry 224
2.2 GPCR-Mediated Presynaptic Regulation of the Release Process Distal to Ca2+ Entry 231
3 Conclusions 250
References 251
Presynaptic Metabotropic Receptors for Acetylcholine and Adrenaline/ Noradrenaline 270
1 Introduction 271
2 Presynaptic Receptors for Acetylcholine 2.1 Acetylcholine Receptor Subtypes 271
2.2 Muscarinic Acetylcholine Receptors 271
3 Presynaptic Receptors for Adrenaline/Noradrenaline 3.1 Adrenoceptor Subtypes 277
3.2 a2 Adrenoceptors 278
3.3 a1 Adrenoceptors 283
3.4 ß Adrenoceptors 286
4 Conclusions 288
References 289
Presynaptic Receptors for Dopamine, Histamine, and Serotonin 298
1 Introduction 299
2 Presynaptic Receptors for Dopamine 301
2.1 Presynaptic Dopamine Autoreceptors: Modulation of Dopamine Release 301
2.2 Presynaptic Dopamine Autoreceptors: Additional Functions 305
2.3 Dopamine Autoreceptors in Disease and Therapy 307
2.4 Presynaptic Dopamine Heteroreceptors on Noradrenergic Terminals 308
2.5 Presynaptic Dopamine Heteroreceptors on Serotonergic Terminals 309
2.6 Presynaptic Dopamine Heteroreceptors on Cholinergic Terminals 309
medium spiny neuron 310
2.7 Presynaptic Dopamine Heteroreceptors on GABAergic Terminals 311
2.8 Presynaptic Dopamine Heteroreceptors on Glutamatergic Terminals 312
2.9 Presynaptic Dopamine Heteroreceptors on Cholecystokinergic Terminals 313
2.10 Presynaptic Dopamine Heteroreceptors in Disease and Therapy 313
3 Presynaptic Receptors for Histamine 314
3.1 Presynaptic Histamine Autoreceptors: Modulation of Release and Synthesis 316
3.2 Histamine Autoreceptors in Disease and Therapy 317
3.3 Presynaptic Histamine Heteroreceptors on Noradrenergic Terminals 317
3.4 Presynaptic Histamine Heteroreceptors on Serotonergic Terminals 318
3.5 Presynaptic Histamine Heteroreceptors on Dopaminergic Terminals 319
3.6 Presynaptic Histamine Heteroreceptors on Cholinergic Terminals 319
3.7 Presynaptic Histamine Heteroreceptors on GABAergic Terminals 320
3.8 Presynaptic Histamine Heteroreceptors on Glutamatergic Terminals 320
3.9 Presynaptic Histamine Heteroreceptors on Peptidergic Terminals 321
3.10 Presynaptic Histamine Heteroreceptors in Disease and Therapy 321
4 Presynaptic Receptors for Serotonin 322
4.1 Presynaptic Serotonin Autoreceptors: Modulation of 5-HT Release 322
4.2 Serotonin Autoreceptors in Disease and Therapy 325
4.3 Presynaptic Serotonin Heteroreceptors on Noradrenergic Terminals 326
4.4 Presynaptic Serotonin Heteroreceptors on Dopaminergic Terminals 327
4.5 Presynaptic Serotonin Heteroreceptors on Cholinergic Terminals 328
4.6 Presynaptic Serotonin Heteroreceptors on GABAergic Terminals 330
4.7 Presynaptic Serotonin Heteroreceptors on Glutamatergic Terminals 330
4.8 Presynaptic Serotonin Heteroreceptors on Glycinergic Terminals 331
4.9 Presynaptic Serotonin Heteroreceptors on Peptidergic Terminals 331
4.10 Presynaptic Serotonin Heteroreceptors in Disease and Therapy 332
References 333
Presynaptic Adenosine and P2Y Receptors 348
1 The Beginning—Purines and Modulation of Neurotransmitter Release 349
2 Adenosine Receptor-Mediated Inhibition of Neurotransmitter Release 2.1 The Receptors Involved 350
2.2 Intracellular Events in A1 Receptor- Mediated Presynaptic Inhibition 352
2.3 Distribution of Presynaptic A1 Receptors 352
2.4 Endogenous Activation of Presynaptic A1 Receptors 353
3 Adenosine Receptor-Mediated Facilitation of Neurotransmitter Release 3.1 The Receptors Involved and Their Distribution 355
3.2 Intracellular Events in A2 Receptor- Mediated Presynaptic Facilitation 355
3.3 Endogenous Activation of Presynaptic A2 Receptors 357
4 P2Y Receptor-Mediated Inhibition of Neurotransmitter Release 4.1 The Receptors Involved 358
4.2 Intracellular Events in P2Y Receptor-Mediated Presynaptic Inhibition 361
4.3 Distribution and Endogenous Activation of Presynaptic P2Y Receptors 362
5 Presynaptic P3 Receptors? 362
6 The Diversity of the Purinergic Mechanisms in the Synaptic Cleft 364
6.1 Release and Inactivation of Purines 364
6.2 Factors That Influence Purine Concentration in the Receptor Biophase 365
7 Adenosine and the Fine-Tuning of Transmitter Release 368
References 370
Presynaptic Metabotropic Glutamate and GABAB Receptors 382
1 Introduction 383
2 Metabotropic Glutamate Autoreceptors 384
2.1 Group I Metabotropic Glutamate Autoreceptors 385
2.2 Group II and Group III Metabotropic Glutamate Autoreceptors 390
3 Metabotropic Glutamate Heteroreceptors 393
3.1 Modulation of Acetylcholine Release 393
3.2 Modulation of Noradrenaline Release 395
4 Presynaptic GABAB Receptors 399
4.1 Structural Characteristics and Distribution of GABAB Rs 399
4.2 Presynaptic GABAB Autoreceptors and Heteroreceptors 400
4.3 Structural Heterogeneity Does not Reflect Pharmacological Heterogeneity 404
4.4 Structural and Functional Diversity Between Presynaptic and Postsynaptic GABAB Receptors 405
4.5 Is Pharmacological Heterogeneity Limited to Presynaptic GABAB Receptors? 407
5 Conclusions and Future Implications 408
References 409
Presynaptic Neuropeptide Receptors 417
1 Introduction 418
2 Presynaptic Opioid Receptors 419
3 Presynaptic Neuropeptide Y Receptors 429
4 Presynaptic ACTH Receptors 434
5 Presynaptic Orexin Receptors 435
References 437
Presynaptic Modulation by Endocannabinoids 443
1 Introduction 444
2 Endocannabinoids and their Receptors 2.1 Endocannabinoid Synthesis and Degradation 446
2.2 The CB1 Receptor 448
2.3 Endocannabinoid Release and Reuptake 448
3 Cannabinoids, Endocannabinoids, and Presynaptic Depression 3.1 Actions of Synthetic Cannabinoids 452
3.2 Endocannabinoid Actions 453
4 Retrograde Endocannabinoid Signaling in Short-Term Synaptic Depression 455
4.1 Depolarization-Induced Suppression of Excitatory and Inhibitory Transmission 455
4.2 Synaptically Driven EC-Dependent Short-Term Depression 459
4.3 Comparison of DSE/I and eSTD 461
5 Endocannabinoid Tone and Intrinsic CB1 Activity 463
6 Endocannabinoid-Dependent Long-Term Synaptic Depression 6.1 EC- LTD Induction Mechanisms 464
6.2 Mechanisms Involved in Maintained Expression of EC-LTD 468
6.3 Endocannabinoids and Cerebellar LTD 468
6.4 Physiological Roles of EC-LTD 470
7 Endocannabinoids and Long-Term Potentiation 470
8 Endocannabinoids, CB1 Receptors, and Behavior 471
8.1 Endocannabinoid and CB1 Roles in Learning and Memory 471
8.2 The Neural Basis of Cannabinoid Intoxication 473
References 474
Presynaptic lonotropic Receptors 486
1 Introduction 487
2 Types of Presynaptic Ionotropic Receptors 490
2.1 Presynaptic Anion Channels 492
2.2 Presynaptic Cation Channels 495
3 Mechanisms of Action 3.1 Spontaneous and Stimulated Release 508
3.2 Excitation-Secretion Coupling 509
3.3 Ionotropic Mechanisms 512
3.4 Metabotropic Mechanisms 515
4 Interactions Between Ionotropic Receptors 517
5 Physiological and Pharmacological Relevance of Presynaptic Ionotropic Receptors 518
6 Conclusion 521
References 521
NO/cGMP-Dependent Modulation of Synaptic Transmission 535
1 Introduction 536
2 Overview of the NO/cGMP Signalling System and Its Expression in the CNS 2.1 Sources of NO and cGMP 537
2.2 cGMP Receptors 538
2.3 cGMP-Independent NO Signalling 542
3 NO and cGMP as Modulators of Synaptic Transmission 3.1 Effects of NO/ cGMP on Transmitter Release 543
3.2 Long-term Potentiation (LTP) and Long-Term Depression ( LTD) as Model Systems to Study NO/ cGMP Signalling in Central Synapses 547
4 Conclusion 556
References 557
Therapeutic Use of Release-Modifying Drugs 567
1 Introduction 568
2 Presynaptic a2 Autoreceptor Agonists and Antagonists 569
2.1 Agonists: Clonidine and Analogs 570
2.2 Antagonists: Mianserin, Mirtazapine, Idazoxan, Efaroxan 570
3 Presynaptic Central Dopamine Autoreceptor Partial Agonist: Aripiprazole 572
4 Presynaptic Peripheral Dopamine Heteroreceptor Agonist: Lergotrile 572
5 Presynaptic 5- HT1D Heteroreceptor Agonists: Sumatriptan and Analogs 572
6 Presynaptic Angiotensin Heteroreceptors: Angiotensin Receptor Antagonists 573
7 Presynaptic ß Autoreceptors: ß Adrenoceptor Antagonists 573
8 Presynaptic Opioid Heteroreceptor Agonists: Morphine and Related Drugs 574
9 Presynaptic Cannabinoid Heteroreceptor Agonists: Cannabis and Related Drugs 574
10 Presynaptic Nicotinic Heteroreceptor Agonists: Nicotine as a Drug of Addiction 574
11 Changes in Sensitivity of Presynaptic Autoreceptors Induced by Antidepressant Drugs 575
12 Conclusions and Future Perspectives 575
References 576
Index 580