Neurotransmitter Transporters (eBook)

Preface 5
List of Contents 7
List of Contributors 9
Zn2+ Modulation of Neurotransmitter Transporters 10
Introduction 11
Synaptic Zn2+ Is a Potential Modulator of Several Neurotransmitter Systems 14
Endogenous Zn2+-Binding Sites in Na+/Cl–-Dependent Neurotransmitter Transporters 16
Endogenous Zn2+- Binding Sites in the Excitatory Amino Acid Transporters 18
Zn2+ Modulation of DAT Function 20
Reversal of Zn2+ Sensitivity by Intracellular Mutations in the DAT 22
Zn2+ Is Found in Presynaptic Vesicles and Is Released Upon Neuronal Stimulation 25
References 27
Molecular Microfluorometry: Converting Arbitrary Fluorescence Units into Absolute Molecular Concentrations to Study Binding Kinetics and Stoichiometry in Transporters 32
Introduction 33
Summary 60
References 61
Structure/Function Relationships in Serotonin Transporter: New Insights from the Structure of a Bacterial Transporter 67
General Background and Significance of SERT 67
Mechanism of Transport 69
Topology 71
The Permeation Pathway 73
The Substrate Binding Site 74
Conformational Changes 75
Future Directions 78
References 79
The Importance of Company: Na+ and Cl– Influence Substrate Interaction with SLC6 Transporters and Other Proteins 82
Introduction 83
Cotransport of Na+ and Cl– with Substrate in SLC6 Family 83
Residues Controlling Na+ Modulation 84
Cl– Binding to Proteins and Cl– Modulation of Transport Proteins 93
Comments on Transporter Residues Governing Na+ and Cl– Modulation of Transport 95
References 96
Currents in Neurotransmitter Transporters 101
Introduction 101
Electrophysiological Background in a Nutshell 104
Coupled and Uncoupled Currents 105
The Single-File Model 106
Transient Currents 107
Leak Current 108
Is There a Physiological Role for Transporter-Associated Currents? 109
Currents and Amphetamines 111
References 114
Mutational Analysis of Glutamate Transporters 118
Glutamate Transporters 119
Ion/Flux Coupling Determines the Concentrating Capacity of the Transporters 119
Uncoupled Ion Currents Associated with Glutamate Transporters 121
The Structure of a Bacterial Glutamate Transporter 122
Mutational Studies of Mammalian Glutamate Transporters 123
A Structural Model for the Transport and Chloride Channel Functions of Glutamate Transporters 135
References 137
The Diverse Roles of Vesicular Glutamate Transporter 3 141
Introduction 141
Vesicular Glutamate Transport 142
Identification of VGLUT3 in Neurons and Glia 146
Conclusion 150
References 151
Extraneuronal Monoamine Transporter and Organic Cation Transporters 1 and 2: A Review of Transport Efficiency 155
Introduction 156
Substrate Specificity 159
Roundup 176
References 179
The Role of SNARE Proteins in Trafficking and Function of Neurotransmitter Transporters 185
Introduction 186
Overview of Syntaxin 1A Regulation of Neurotransmitter Transporters 190
Details of Syntaxin 1A Regulation of GAT1 192
Syntaxin 1A Regulation of SERT Conducting States 195
Conclusions 197
References 197
Regulation of the Dopamine Transporter by Phosphorylation 201
Introduction to the Dopamine Transporter 202
Dopamine Transporter Phosphorylation 204
Future Perspectives 213
References 214
The Dopamine Transporter: A Vigilant Border Control for Psychostimulant Action 219
Introduction: Dopamine Transmission and Psychostimulants 220
Ion Channel-Like Behavior of the DAT 222
Regulation of DAT Function by Its Substrates 225
Regulation of DAT Function by Its Inhibitors 228
Dopamine D2 Receptor Modulation of DAT Function 229
Summary 230
References 231
Oligomerization of Neurotransmitter Transporters: A Ticket from the Endoplasmic Reticulum to the Plasma Membrane 237
Oligomerization of Neurotransmitter Transporters 238
The ER Export 241
Oligomerization and ER Export 244
References 249
Acute Regulation of Sodium-Dependent Glutamate Transporters: A Focus on Constitutive and Regulated Trafficking 254
Introduction 255
Characteristics of Na+- Dependent Glutamate Transporters 257
Rapid Regulation of Glutamate Transporters 260
Conclusions 273
References 273
Regulation and Dysregulation of Glutamate Transporters 279
Introduction 280
Regulation of Glutamate Transporters 283
Dysregulation of Glutamate Transporters 296
Conclusions 298
References 299
Regulation of Vesicular Monoamine and Glutamate Transporters by Vesicle- Associated Trimeric G Proteins: New Jobs for Long- Known Signal Transduction Molecules 306
Introduction 307
Secretory Vesicles and Their Neurotransmitter Transporters 307
Factors Influencing Transmitter Content of Individual Vesicles 310
Heterotrimeric G Proteins on Secretory Vesicles 311
Differences in the Regulation of VMAT and VGLUT Activities 313
Conclusions 321
References 322
Human Genetics and Pharmacology of Neurotransmitter Transporters 327
The Human Dopamine Transporter 328
The Human Serotonin Transporter 343
The Human Norepinephrine Transporter 351
Transporter Gene Knockout Mice: Implications 356
Summary 357
References 357
ADHD and the Dopamine Transporter: Are There Reasons to Pay Attention? 372
Overview of ADHD 373
The Human Dopamine Transporter 379
DAT Transgenics as Animal Models of ADHD 387
Neuroimaging DAT in Human Subjects 389
Genetic Linkage in ADHD and the Impact of DAT Gene Variants 393
References 402
Inactivation of 5HT Transport in Mice: Modeling Altered 5HT Homeostasis Implicated in Emotional Dysfunction, Affective Disorders, and Somatic Syndromes 415
Introduction 416
Basic Features of 5HT Transporter Gene Inactivation 419
Brain Development and Plasticity 428
Gene–Gene Interaction 430
Inactivation as a Model for Serotonin-Related Somatic Disorders 432
Alcohol and Other Substances of Abuse 435
Linking 5HTT to Affective Spectrum Disorders 437
Gene–Environment Interaction 440
Molecular Imaging of Emotionality: 442
A Risk Assessment Strategy for Depression? 442
References 445
Lessons from the Knocked-Out Glycine Transporters 455
Neurotransmitter Functions of Glycine in the CNS 456
GlyTs Are Members of the Na+/Cl--Dependent Transporter Family 457
Distribution of GlyTs in the CNS 462
Functional Roles of GlyTs 465
GlyTs and Human Diseases 473
Conclusions and Perspectives 475
References 476
The Norepinephrine Transporter in Physiology and Disease 482
Introduction 483
Properties, Physiology and Pharmacology of the NET 484
Tissue Expression 490
Regulation of NET Function and Expression 491
Structure–Function Relationship 494
Gene Structure, Promoter and Alternative Splicing 498
hNET: Significance in Disease, Therapy and Diagnosis 499
References 509
The High-Affinity Choline Transporter: A Critical Protein for Sustaining Cholinergic Signaling as Revealed in Studies of Genetically Altered Mice 522
CHT Function and Regulation 523
CHT and Genetic Mouse Models of Cholinergic Dysfunction 528
CHT+/- Mice asModels of Cholinergic Dysfunction 534
References 537
Subject Index 542