Sitte / Freissmuth Neurotransmitter Transporters

1. Auflage 2006
ISBN: 978-3-540-29784-0
Verlag: Springer Berlin Heidelberg
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 175, 549 Seiten

Reihe: Handbook of Experimental Pharmacology

This book is a representative survey of the current status of the structure, function, regulation and molecular pharmacology of Neurotransmitter Transporters. It provides an overview of insights generated in the past five years. The volume serves as a useful compendium of current concepts and an inspiring starting point. It is a source for students interested in this emerging field as well as for experienced scientists looking for an update.

Autoren/Hrsg.

Sitte, Harald

Freissmuth, Michael

Inhaltsverzeichnis

1;Preface;5
2;List of Contents;7
3;List of Contributors;9
4;Zn2+ Modulation of Neurotransmitter Transporters;10
4.1;Introduction;11
4.2;Synaptic Zn2+ Is a Potential Modulator of Several Neurotransmitter Systems;14
4.3;Endogenous Zn2+-Binding Sites in Na+/Cl–-Dependent Neurotransmitter Transporters;16
4.4;Endogenous Zn2+- Binding Sites in the Excitatory Amino Acid Transporters;18
4.5;Zn2+ Modulation of DAT Function;20
4.6;Reversal of Zn2+ Sensitivity by Intracellular Mutations in the DAT;22
4.7;Zn2+ Is Found in Presynaptic Vesicles and Is Released Upon Neuronal Stimulation;25
4.8;References;27
5;Molecular Microfluorometry: Converting Arbitrary Fluorescence Units into Absolute Molecular Concentrations to Study Binding Kinetics and Stoichiometry in Transporters;32
5.1;Introduction;33
5.2;Summary;60
5.3;References;61
6;Structure/Function Relationships in Serotonin Transporter: New Insights from the Structure of a Bacterial Transporter;67
6.1;General Background and Significance of SERT;67
6.2;Mechanism of Transport;69
6.3;Topology;71
6.4;The Permeation Pathway;73
6.5;The Substrate Binding Site;74
6.6;Conformational Changes;75
6.7;Future Directions;78
6.8;References;79
7;The Importance of Company: Na+ and Cl– Influence Substrate Interaction with SLC6 Transporters and Other Proteins;82
7.1;Introduction;83
7.2;Cotransport of Na+ and Cl– with Substrate in SLC6 Family;83
7.3;Residues Controlling Na+ Modulation;84
7.4;Cl– Binding to Proteins and Cl– Modulation of Transport Proteins;93
7.5;Comments on Transporter Residues Governing Na+ and Cl– Modulation of Transport;95
7.6;References;96
8;Currents in Neurotransmitter Transporters;101
8.1;Introduction;101
8.2;Electrophysiological Background in a Nutshell;104
8.3;Coupled and Uncoupled Currents;105
8.4;The Single-File Model;106
8.5;Transient Currents;107
8.6;Leak Current;108
8.7;Is There a Physiological Role for Transporter-Associated Currents?;109
8.8;Currents and Amphetamines;111
8.9;References;114
9;Mutational Analysis of Glutamate Transporters;118
9.1;Glutamate Transporters;119
9.2;Ion/Flux Coupling Determines the Concentrating Capacity of the Transporters;119
9.3;Uncoupled Ion Currents Associated with Glutamate Transporters;121
9.4;The Structure of a Bacterial Glutamate Transporter;122
9.5;Mutational Studies of Mammalian Glutamate Transporters;123
9.6;A Structural Model for the Transport and Chloride Channel Functions of Glutamate Transporters;135
9.7;References;137
10;The Diverse Roles of Vesicular Glutamate Transporter 3;141
10.1;Introduction;141
10.2;Vesicular Glutamate Transport;142
10.3;Identification of VGLUT3 in Neurons and Glia;146
10.4;Conclusion;150
10.5;References;151
11;Extraneuronal Monoamine Transporter and Organic Cation Transporters 1 and 2: A Review of Transport Efficiency;155
11.1;Introduction;156
11.2;Substrate Specificity;159
11.3;Roundup;176
11.4;References;179
12;The Role of SNARE Proteins in Trafficking and Function of Neurotransmitter Transporters;185
12.1;Introduction;186
12.2;Overview of Syntaxin 1A Regulation of Neurotransmitter Transporters;190
12.3;Details of Syntaxin 1A Regulation of GAT1;192
12.4;Syntaxin 1A Regulation of SERT Conducting States;195
12.5;Conclusions;197
12.6;References;197
13;Regulation of the Dopamine Transporter by Phosphorylation;201
13.1;Introduction to the Dopamine Transporter;202
13.2;Dopamine Transporter Phosphorylation;204
13.3;Future Perspectives;213
13.4;References;214
14;The Dopamine Transporter: A Vigilant Border Control for Psychostimulant Action;219
14.1;Introduction: Dopamine Transmission and Psychostimulants;220
14.2;Ion Channel-Like Behavior of the DAT;222
14.3;Regulation of DAT Function by Its Substrates;225
14.4;Regulation of DAT Function by Its Inhibitors;228
14.5;Dopamine D2 Receptor Modulation of DAT Function;229
14.6;Summary;230
14.7;References;231
15;Oligomerization of Neurotransmitter Transporters: A Ticket from the Endoplasmic Reticulum to the Plasma Membrane;237
15.1;Oligomerization of Neurotransmitter Transporters;238
15.2;The ER Export;241
15.3;Oligomerization and ER Export;244
15.4;References;249
16;Acute Regulation of Sodium-Dependent Glutamate Transporters: A Focus on Constitutive and Regulated Trafficking;254
16.1;Introduction;255
16.2;Characteristics of Na+- Dependent Glutamate Transporters;257
16.3;Rapid Regulation of Glutamate Transporters;260
16.4;Conclusions;273
16.5;References;273
17;Regulation and Dysregulation of Glutamate Transporters;279
17.1;Introduction;280
17.2;Regulation of Glutamate Transporters;283
17.3;Dysregulation of Glutamate Transporters;296
17.4;Conclusions;298
17.5;References;299
18;Regulation of Vesicular Monoamine and Glutamate Transporters by Vesicle- Associated Trimeric G Proteins: New Jobs for Long- Known Signal Transduction Molecules;306
18.1;Introduction;307
18.2;Secretory Vesicles and Their Neurotransmitter Transporters;307
18.3;Factors Influencing Transmitter Content of Individual Vesicles;310
18.4;Heterotrimeric G Proteins on Secretory Vesicles;311
18.5;Differences in the Regulation of VMAT and VGLUT Activities;313
18.6;Conclusions;321
18.7;References;322
19;Human Genetics and Pharmacology of Neurotransmitter Transporters;327
19.1;The Human Dopamine Transporter;328
19.2;The Human Serotonin Transporter;343
19.3;The Human Norepinephrine Transporter;351
19.4;Transporter Gene Knockout Mice: Implications;356
19.5;Summary;357
19.6;References;357
20;ADHD and the Dopamine Transporter: Are There Reasons to Pay Attention?;372
20.1;Overview of ADHD;373
20.2;The Human Dopamine Transporter;379
20.3;DAT Transgenics as Animal Models of ADHD;387
20.4;Neuroimaging DAT in Human Subjects;389
20.5;Genetic Linkage in ADHD and the Impact of DAT Gene Variants;393
20.6;References;402
21;Inactivation of 5HT Transport in Mice: Modeling Altered 5HT Homeostasis Implicated in Emotional Dysfunction, Affective Disorders, and Somatic Syndromes;415
21.1;Introduction;416
21.2;Basic Features of 5HT Transporter Gene Inactivation;419
21.3;Brain Development and Plasticity;428
21.4;Gene–Gene Interaction;430
21.5;Inactivation as a Model for Serotonin-Related Somatic Disorders;432
21.6;Alcohol and Other Substances of Abuse;435
21.7;Linking 5HTT to Affective Spectrum Disorders;437
21.8;Gene–Environment Interaction;440
21.9;Molecular Imaging of Emotionality:;442
21.10;A Risk Assessment Strategy for Depression?;442
21.11;References;445
22;Lessons from the Knocked-Out Glycine Transporters;455
22.1;Neurotransmitter Functions of Glycine in the CNS;456
22.2;GlyTs Are Members of the Na+/Cl--Dependent Transporter Family;457
22.3;Distribution of GlyTs in the CNS;462
22.4;Functional Roles of GlyTs;465
22.5;GlyTs and Human Diseases;473
22.6;Conclusions and Perspectives;475
22.7;References;476
23;The Norepinephrine Transporter in Physiology and Disease;482
23.1;Introduction;483
23.2;Properties, Physiology and Pharmacology of the NET;484
23.3;Tissue Expression;490
23.4;Regulation of NET Function and Expression;491
23.5;Structure–Function Relationship;494
23.6;Gene Structure, Promoter and Alternative Splicing;498
23.7;hNET: Significance in Disease, Therapy and Diagnosis;499
23.8;References;509
24;The High-Affinity Choline Transporter: A Critical Protein for Sustaining Cholinergic Signaling as Revealed in Studies of Genetically Altered Mice;522
24.1;CHT Function and Regulation;523
24.2;CHT and Genetic Mouse Models of Cholinergic Dysfunction;528
24.3;CHT+/- Mice asModels of Cholinergic Dysfunction;534
24.4;References;537
25;Subject Index;542