Molecular Biology of RGS Proteins

1. Auflage 2009
ISBN: 978-0-08-091197-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 508 Seiten

Molecular Biology of RGS Proteins, a volume of Progress in Molecular Biology and Translational Science, will include historical discussion of RGS proteins, the role of RGS proteins in addiction, depression and Parkinson's disease and the biology and functional regulation of RGS9 isoforms. This publication further discusses RGS proteins in cellular signaling, protein control in lymphocyte function, and alternative splicing of RGS transcripts and nuclear RGS proteins, offering the latest in research of RGS proteins.

Autoren/Hrsg.

Inhaltsverzeichnis

1;Front Cover
;1
2;Progress in
Molecular Biology and Translational Science ;4
3;Copyright Page
;5
4;Contents
;6
5;Contributors
;12
6;Preface
;14
7;Chapter 1: RGS Proteins: The Early Days;16
7.1;I. Reflection;16
7.2;II. Identification;18
7.3;III. Function;20
7.4;IV. Family;21
7.5;V. Mechanism;23
7.6;VI. Structure;25
7.7;VII. Perspective;25
7.8;References;26
8;Chapter 2: Insights into RGS Protein Function from Studies in Caenorhabditis elegans
;30
8.1;I. Introduction;31
8.1.1;A. C. elegans as a Model Organism for the Analysis of Molecular Mechanisms;31
8.1.2;B. G Protein Signaling and RGS Proteins in C. elegans;31
8.2;II. Experimental Approaches for Identifying the Functions of C. elegans RGS Proteins;38
8.3;III. The Physiological Roles of Specific RGS Proteins in C. elegans;41
8.3.1;A. RGS Proteins That Function in C. elegans Development;41
8.3.2;B. RGS Proteins That Function in the Adult C. elegans Nervous System;43
8.4;IV. Principles of RGS Function That Emerge from Studies in C. elegans;46
8.4.1;A. The In Vivo Specificity of RGS Proteins to Galpha-Subunits
;47
8.4.2;B. Multiple RGS Proteins Can Regulate One Galpha-Subunit
;48
8.4.3;C. Determining the Requirement for Multiple Domains in One RGS Protein;51
8.4.4;D. The Unconventional Heterotrimer Model for R7 RGS Protein Function;53
8.5;V. Remaining Questions Regarding the In Vivo Functions of RGS Proteins;56
8.5.1;A. What is the In Vivo Function of the Remaining C. elegans RGS Proteins?;56
8.5.2;B. Why Do RGS Proteins Exist?;57
8.6;References;58
9;Chapter 3: Regulators of G Protein Signaling Proteins as Central Components of G Protein-Coupled Receptor Signaling Complexes;64
9.1;I. Introduction;65
9.2;II. Overview of RGS Proteins;65
9.2.1;A. RGS Protein Structure Determines Function;66
9.3;III. RGS Protein Interactions with GPCRs;67
9.3.1;A. GPCRs Interact Directly with RGS Proteins;69
9.3.2;B. Indirect GPCR/RGS Protein Interactions;72
9.3.3;C. Implied RGS Protein and GPCR Interactions;74
9.3.4;D. RGS Proteins also Interact with Non-GPCR Receptors and Ion Channels;76
9.3.5;E. Factors that Dictate RGS Protein Localization at the Plasma Membrane;77
9.4;IV. GPCRs Serve as Platforms for Molecular Signaling;78
9.5;V. Summary and Perspectives;81
9.6;References;82
10;Chapter 4: Structure and Function of Regulator of G Protein Signaling Homology Domains;90
10.1;I. Introduction;91
10.2;II. The Canonical RH Domain;92
10.3;III. The RGS Protein RH Domain;98
10.3.1;A. Signaling Context;98
10.3.2;B. Galpha Binding, GAP Activity, and Selectivity
;98
10.3.3;C. Ternary Complexes of RGS Proteins, Galpha Subunits, and Effectors
;102
10.3.4;D. Interface of RGS9 with Gbeta5: An RH Domain in a Modular Setting
;103
10.3.5;E. Other Interaction Sites;104
10.4;IV. The Axin RH Domain;105
10.4.1;A. Signaling Context;105
10.4.2;B. Structural Adaptations of the Axin RH Domain;105
10.4.3;C. Interaction with APC;105
10.5;V. The RhoGEF RH Domain;106
10.5.1;A. Signaling Context;106
10.5.2;B. Structural Adaptations of the RhoGEF RH Domain;107
10.5.3;C. Interaction with the Effector Site of Galpha13
;108
10.6;VI. The GRK RH Domain;109
10.6.1;A. Signaling Context;109
10.6.2;B. Structural Adaptations of the GRK RH Domain;110
10.6.3;C. Interaction with the Kinase Domain;112
10.6.4;D. Interaction with the PH Domain;113
10.6.5;E. Interaction with Galphaq
;114
10.7;VII. Structurally Uncharacterized RH Domains;115
10.7.1;A. Two Tandem RH Domains in D-AKAP2;116
10.7.2;B. The Sorting Nexins;116
10.7.3;C. RGSL ``Family´´ RH Domains;117
10.8;VIII. Perspectives;117
10.9;References;120
11;Chapter 5: Nuclear Trafficking of Regulator of G Protein Signaling Proteins and Their Roles in the Nucleus
;130
11.1;I. Introduction;131
11.2;II. Subcellular Localization of RGS Proteins;132
11.3;III. Nuclear Trafficking of RGS Proteins;136
11.3.1;A. Mechanisms Controlling Protein Nucleocytoplasmic Transport;136
11.3.2;B. NLSs and NESs in RGS Proteins;137
11.3.3;C. Posttranslational Modifications of RGS Proteins that Affect Their Nuclear Trafficking;145
11.3.4;D. Binding Partners Affecting Nuclear Trafficking of RGS Proteins;148
11.4;IV. Potential Roles of RGS Proteins in the Nucleus;153
11.4.1;A. RGS Proteins in Cell Death;154
11.4.2;B. RGS Proteins in Cell Cycle Regulation and Cell Division;154
11.4.3;C. RGS Proteins in Transcription Regulation;156
11.4.4;D. RGS Protein in Stress Response;160
11.4.5;E. RGS Proteins in Nuclear G Protein Signaling;162
11.5;V. Conclusions;162
11.6;References;163
12;Chapter 6: Structure, Function, and Localization of Gbeta5-RGS Complexes
;172
12.1;I. Introduction;173
12.1.1;A. G Proteins, RGS Proteins, and R7 Family;173
12.1.2;B. Gbeta5 is a Unique G Protein beta Subunit That Interacts with RGS Proteins of the R7 Family;174
12.2;II. Structure of Gbeta5-R7 Complexes. The Role of RGS, GGL, and DEP Domains;176
12.2.1;A. Multidomain Organization of Gbeta5-R7 Complexes;176
12.2.2;B. RGS Domain and GAP Activity;179
12.2.3;C. The Role of Gbeta5 within the Complex;180
12.2.4;D. Function of the DEP Domain;183
12.2.5;E. Other Binding Partners of the DEP Domain;185
12.3;III. Expression and Subcellular Localization of Gbeta5-R7 Proteins;188
12.3.1;A. Regional Expression of R7 Family in the CNS;188
12.3.2;B. Expression of R7 Family RGS Proteins in the Retina;190
12.3.3;C. Do Peripheral Tissues Express R7 Family RGS Proteins?;191
12.3.4;D. Regulation of R7 Family Expression;193
12.3.5;E. Subcellular Localization of Gbeta5-R7 Proteins;195
12.3.6;F. Molecular Mechanisms of Gbeta5-R7 Membrane Association;196
12.3.7;G. Nuclear Localization of Gbeta5-R7 Complexes;197
12.3.8;H. R7 Family Membrane Anchoring Proteins, R7BP, and R9AP;200
12.4;IV. Other Protein-Protein Interactions and Phosphorylation of R7 Family Proteins;205
12.5;V. Physiological Role of Gbeta5-R7 Complexes: A Brief Summary of In Vivo Studies;207
12.6;VI. Conclusions;208
12.7;References;209
13;Chapter 7: Biology and Functions of the RGS9 Isoforms;220
13.1;I. Introductory Remarks;221
13.2;II. RGS9 Exists as Two Splice Isoforms with Distinct Nonoverlapping Expression Patterns;221
13.3;III. RGS9 Isoforms are Modular Multidomain Proteins;222
13.4;IV. Gbeta5 is an Obligatory Subunit of RGS9;223
13.5;V. The DEP Domain Mediates RGS9 Association with a Novel Class of Membrane Anchors;224
13.6;VI. The PGL Domain is the Unique Structural Feature of the RGS9-2 Isoform;224
13.7;VII. Spatial Organization of the RGS9Gbeta5 Complex;225
13.8;VIII. RGS9-2Gbeta5SR7BP Regulates G Protein Signaling in the Striatum;226
13.9;IX. RGS9-1Gbeta5LR9AP Regulates Visual Signal Transduction in Vertebrate Photoreceptors;228
13.10;X. The Role of the Effector Enzyme in Regulating Transducin GTPase and the Concept of Affinity Adapters;231
13.11;XI. Comparing the Functional Properties of RGS9 Isoforms Expressed in the Same Cell Type Suggests a Hypothesis on the Evolutionary Origin of Phototransduction
;233
13.12;XII. Mechanisms Regulating the Galpha Recognition Selectivity and Catalytic Activity of RGS9
;234
13.13;Acknowledgments
;236
13.14;References;236
14;Chapter 8: The Role of Gbeta5 in Vision;244
14.1;I. Introduction;244
14.2;II. The Biochemistry of Gbeta5;245
14.3;III. An Overview of the Visual System;250
14.4;IV. RGS9-1 Expression Level Determines the Duration of Rod Phototransduction;252
14.5;V. The Involvement of Gbeta5S/R7RGS in the mGluR6 Pathway in ON-Bipolar Cells;254
14.6;VI. Spontaneous Retinal Activity and Retinogeniculate Projections;256
14.7;VII. Future Directions;258
14.8;References;259
15;Chapter 9: Regulation of Immune Function by G Protein-Coupled Receptors, Trimeric G Proteins, and RGS Proteins
;264
15.1;I. Introduction;265
15.2;II. G Protein-Coupled Receptors;267
15.2.1;A. Gi- and Gq-Coupled Receptors;267
15.2.2;B. Gs-Coupled Receptors;272
15.2.3;C. G12/13-Coupled Receptors;273
15.3;III. Heterotrimeric G Proteins;275
15.3.1;A. Gi Subfamily;275
15.3.2;B. Gq Subfamily;277
15.3.3;C. Gs Subfamily;278
15.3.4;D. G12/13 Subfamily;278
15.3.5;E. Gbetagamma;280
15.4;IV. RGS Proteins;280
15.4.1;A. Modulation of RGS Protein Expression;281
15.4.2;B. Analysis of Genetically Modified Mice;281
15.5;V. Heterotrimeric G Protein- and RGS Protein-Mediated Modulation of Lymphocyte Migration and Trafficking;284
15.5.1;A. Gi-Mediated Control of Lymphocyte Trafficking;284
15.5.2;B. RGS Protein-Mediated Regulation of Lymphocyte Trafficking;286
15.6;VI. Downstream Signaling Events and Regulatory Proteins in Heterotrimeric G Protein-Mediated Cell Migration;287
15.6.1;A. Signaling Network in Dictyostelium, Neutrophils, and Other Cell Types;287
15.6.2;B. Downstream Signaling Events in Lymphocyte Migration;292
15.7;VII. Spatiotemporal Dynamics of Heterotrimeric G Protein Signaling Components in Migrating Cells;296
15.8;VIII. Conclusions;298
15.9;Acknowledgments;298
15.10;References;298
16;Chapter 10: Regulators of G Protein Signaling in Neuropsychiatri
c Disorders;314
16.1;I. G Protein-Coupled Receptors (GPCRs) and CNS Disorders;315
16.2;II. The Diverse Family of RGS Proteins;315
16.3;III. RGS Protein Expression in the Brain;316
16.4;IV. RGS9-2 and Drug Addiction;317
16.5;V. RGS9-2 and Parkinson's Disease;320
16.6;VI. RGS7 in Addiction and Anxiety Disorders;322
16.7;VII. The RZ Family Members Modulate Opioidergic and Dopaminergic Responses;325
16.8;VIII. RGS2 in Anxiety Disorders;327
16.9;IX. RGS2 in Schizophrenia;328
16.10;X. RGS4 and Scizophrenia;330
16.11;XI. RGS4 in Nociception, Analgesia, and Addiction;337
16.12;XII. Regulators of G Protein Signaling and Neuronal Survival;340
16.13;XIII. RGS Proteins as Drug Targets;341
16.14;XIV. Summary;341
16.15;References;341
17;Chapter 11: Identification of Ligands Targeting RGS Proteins: High-Throughput Screening and Therapeutic Potential;350
17.1;I. Introduction;351
17.1.1;A. Genetic Mouse Models;351
17.1.2;B. RGS Proteins as Drug Targets;353
17.2;II. Targeting RGS Proteins;354
17.2.1;A. The RH Domain;354
17.3;III. Rationally Designed RGS Inhibitors;355
17.4;IV. HTS for RGS Ligands;356
17.4.1;A. Flow Cytometry Protein Interaction Assay (FCPIA) and CCG-4986;356
17.4.2;B. Multiplex FCPIA;357
17.4.3;C. High-Throughput Flow Cytometry;358
17.4.4;D. Differential Scanning Fluorimetry;359
17.4.5;E. Yeast-Based Screening Methods;359
17.4.6;F. Peptide Library Screening Methods;360
17.4.7;G. RGS Modulator Peptides;361
17.4.8;H. Capillary Electrophoresis Methods;362
17.5;V. Unique Compounds;363
17.6;VI. Targeting Accessory Domains;364
17.7;VII. Conclusions;365
17.8;References;366
18;Index
;372
19;Color Plate
;382