Biology of the NMDA Receptor

Excerpt

This book covers many aspects of the biology of NMDARs: their role in controlling structure and function of synapses and neurons during early development; how overstimulation of NMDARs results in excitotoxicity and contributes to several progressive brain disorders, including Huntington’s disease; the newly discovered and intriguing interactions of NMDARs and dopamine receptors that mediate reward in the central nervous system; the role of NMDARs in alcohol dependence and the promise of NMDAR-based therapeutics for treating alcoholism; how functional expression is controlled at the level of gene transcription by several families of transcription factors; how NMDAR activation regulates local synaptic protein synthesis required for long-term changes in synaptic strength; the modulation of NMDAR function by signaling cascades cumulating in activation of protein kinases and phosphatases; the importance of cellular mechanisms underlying trafficking and targeting of NMDAR protein for many of its physiological functions; how NMDAR-mediated calcium signaling in dendritic spines controls synaptic efficacy and spine morphology; the roles NMDARs play in different temporal phases of memory formation in Drosophila; the extracellular modulation of NMDARs by polyamines, subunit-specific inhibitors, zinc ions, and pH, and the structural bases for their effects; a detailed description of NMDAR pharmacology, structure–activity relationships of agonists and antagonists, and roads to therapeutic drug design; the physiological roles played by NMDARs and their molecular structures; NMDAR activation mechanisms and the therapeutic potential of allosteric modulators; and the novel role of presynaptically localized NMDARs in controlling synaptic plasticity.

Contents

• Series Preface
• Preface
• About the Editor
• Contributors
• 1. NMDA Receptors and Brain Development
  Rebecca C. Ewald and Hollis T. Cline.
  • 1.1 INTRODUCTION
  • 1.2 DEVELOPMENTAL EXPRESSION PATTERNS OF NMDA RECEPTORS
  • 1.3 NMDA RECEPTORS AND STRUCTURAL DEVELOPMENT OF NEURONS
  • 1.4 NMDA RECEPTORS AND ACTIVITY-DEPENDENT DEVELOPMENT OF GLUTAMATERGIC SYNAPSES
  • 1.5 CONCLUDING REMARKS
  • REFERENCES
• 2. NMDA Receptors and Huntington’s Disease
  Herman B. Fernandes and Lynn A. Raymond.
  • 2.1 HUNTINGTON’S DISEASE
  • 2.2 MODEL SYSTEMS FOR STUDY OF NMDA RECEPTOR FUNCTION IN HD
  • 2.3 EXCITOTOXICITY HYPOTHESIS IN HD PATHOGENESIS
  • 2.4 DOWNSTREAM CONSEQUENCES OF NMDA RECEPTOR ACTIVATION IN CELLS EXPRESSING MHTT
  • 2.5 ALTERATIONS OF NMDA RECEPTOR-MEDIATED SYNAPTIC TRANSMISSION AND PLASTICITY IN HD
  • 2.6 POSSIBLE MECHANISMS FOR MODULATION OF NMDA RECEPTOR FUNCTION BY MHTT
  • 2.7 SUMMARY
  • REFERENCES
• 3. NMDA and Dopamine: Diverse Mechanisms Applied to Interacting Receptor Systems
  Carlos Cepeda, Véronique M. André, Emily L. Jocoy, and Michael S. Levine.
  • 3.1 INTRODUCTION
  • 3.2 CLASSIFICATION AND MORPHOLOGICAL BASIS FOR INTERACTIONS AMONG GLUTAMATE AND DA RECEPTOR SUBTYPES
  • 3.3 DA AND D1 RECEPTOR ENHANCEMENT OF NMDA RECEPTOR-MEDIATED RESPONSES
  • 3.4 RECIPROCAL D1–NMDA RECEPTOR INTERACTIONS
  • 3.5 TOPOGRAPHIC AND TEMPORAL ASPECTS OF D1–NMDA OCCURS RECEPTOR INTERACTIONS
  • 3.6 REDUCTION OF NMDA RECEPTOR-MEDIATED RESPONSES BY DA OCCURS VIA D2 RECEPTORS
  • 3.7 GENETIC MANIPULATIONS OF DA–NMDA RECEPTOR INTERACTIONS
  • 3.8 FUNCTIONAL RELEVANCE OF DA–NMDA RECEPTOR INTERACTIONS
  • 3.9 CONCLUSIONS
  • REFERENCES
• 4. The NMDA Receptor and Alcohol Addiction
  Dorit Ron and Jun Wang.
  • 4.1 INTRODUCTION
  • 4.2 ACUTE ETHANOL INHIBITION OF NMDA RECEPTOR FUNCTION
  • 4.3 FACILITATION OF NMDA RECEPTOR FUNCTION BY ETHANOL
  • 4.4 PHYSIOLOGICAL IMPLICATIONS OF MODULATION OF NMDA RECEPTOR FUNCTION BY ETHANOL
  • 4.5 NMDA RECEPTORS AND BEHAVIORS ASSOCIATED WITH ETHANOL EXPOSURE
  • 4.6 MODULATORS OF NMDA RECEPTOR FUNCTION AND TREATMENT OF ALCOHOL ABUSE AND DEPENDENCE
  • REFERENCES
• 5. Transcriptional Regulation of NMDA Receptor Expression
  Guang Bai and Peter W. Hoffman.
  • 5.1 INTRODUCTION
  • 5.2 IDENTIFICATION OF PROMOTER
  • 5.3 REGULATORY UNITS: CIS ELEMENTS AND TRANS FACTORS
  • 5.4 DEVELOPMENTAL EXPRESSION OF NR GENES
  • 5.5 GROWTH FACTOR REGULATION OF NR GENES
  • 5.6 CELL TYPE SPECIFICITY OF NR GENE EXPRESSION
  • 5.7 NEUROLOGICAL DISORDERS
  • 5.8 EPIGENETIC REGULATION
  • 5.9 SUMMARY
  • REFERENCES
• 6. NMDA Receptors and Translational Control
  Charles A. Hoeffer and Eric Klann.
  • 6.1 INTRODUCTION
  • 6.2 OVERVIEW OF TRANSLATION
  • 6.3 THREE STAGES OF TRANSLATION
  • 6.4 RNA BINDING PROTEINS AND mRNA LOCALIZATION
  • 6.5 ADMINISTERING TRANSLATION: NMDA RECEPTOR-DEPENDENT SIGNALING TO TRANSLATIONAL MACHINERY
  • 6.6 NMDA RECEPTORS AND REGULATION OF TRANSLATIONAL SUBSTRATES
  • 6.7 CONCLUDING THOUGHTS
  • REFERENCES
• 7. Regulation of NMDA Receptors by Kinases and Phosphatases
  Michael W. Salter, Yina Dong, Lorraine V. Kalia, Xue Jun Liu, and Graham Pitcher.
  • 7.1 INTRODUCTION
  • 7.2 NMDA RECEPTOR REGULATION BY SERINE AND THREONINE KINASES AND PHOSPHATASES
  • 7.3 REGULATION OF NMDA RECEPTORS BY PROTEIN TYROSINE KINASES AND PHOSPHATASES
  • 7.4 NMDA RECEPTOR PHOSPHORYLATION IN SYNAPTIC PLASTICITY
  • 7.5 NMDA RECEPTOR PHOSPHORYLATION IN CENTRAL NERVOUS SYSTEM PATHOLOGY
  • 7.6 CONCLUSIONS
  • REFERENCES
• 8. Trafficking and Targeting of NMDA Receptors
  Ronald S. Petralia, Rana A. Al-Hallaq, and Robert J. Wenthold.
  • 8.1 INTRODUCTION
  • 8.2 NMDA RECEPTOR TRANSPORT THROUGH THE BIOSYNTHETIC PATHWAY, AT THE SYNAPSE, AND FOLLOWING INTERNALIZATION
  • 8.3 NMDA RECEPTOR TRAFFICKING AND DISEASE
  • REFERENCES
• 9. NMDA Receptor-Mediated Calcium Transients in Dendritic Spines
  Brenda L. Bloodgood and Bernardo L. Sabatini.
  • 9.1 Introduction
  • 9.2 SUBUNIT DEPENDENCE Of NMDA RECEPTOR-MEDIATED CALCIUM INFLUX
  • 9.3 PHOSPHORYLATION-DEPENDENT REGULATION OF NMDA RECEPTOR-DEPENDENT CALCIUM ENTRY
  • 9.4 VOLTAGE-DEPENDENT REGULATION OF SYNAPTICALLY EVOKED CALCIUM INFLUX
  • 9.5 POSSIBLE EFFECTS OF COMPARTMENTALIZED ELECTRICAL SIGNALING ON NMDA RECEPTORS
  • 9.6 IMPACT OF SPINE MORPHOLOGY ON CALCIUM SIGNALING IN DENDRITIC SPINES
  • 9.7 CONCLUSION
  • REFERENCES
• 10. NMDA Receptors in Drosophila
  Shouzhen Xia and Ann-Shyn Chiang.
  • 10.1 INTRODUCTION
  • 10.2 NMDA RECEPTOR HOMOLOGUES IN DROSOPHILA
  • 10.3 FUNCTIONAL EXPRESSION OF FLY NMDA RECEPTORS
  • 10.4 EXPRESSION OF FLY NMDA RECEPTORS IN ADULT BRAIN
  • 10.5 NMDA RECEPTOR-DEPENDENT LEARNING AND LONG-TERM MEMORY CONSOLIDATION
  • 10.6 LOCALIZATION OF NMDA RECEPTOR-DEPENDENT MEMORIES
  • 10.7 NMDA RECEPTORS IN OTHER INVERTEBRATES
  • 10.8 SUMMARY
  • REFERENCES
• 11. Extracellular Modulation of NMDA Receptors
  Keith Williams.
  • 11.1 INTRODUCTION
  • 11.2 POLYAMINES
  • 11.3 STRUCTURES OF NMDA RECEPTOR SUBUNITS AND RELEVANCE TO THE POLYAMINE SITE
  • 11.4 IFENPRODIL
  • 11.5 STRUCTURES OF NMDA RECEPTOR SUBUNITS AND RELEVANCE TO THE IFENPRODIL SITE
  • 11.6 ZINC IONS
  • 11.7 STRUCTURES OF NMDA RECEPTOR SUBUNITS AND RELEVANCE TO THE ZN²⁺ SITE
  • 11.8 PROTONS AND EXTRACELLULAR pH
  • 11.9 WHITHER NEXT?
  • REFERENCES
• 12. Pharmacology of NMDA Receptors
  Daniel T. Monaghan and David E. Jane.
  • 12.1 INTRODUCTION
  • 12.2 PHARMACOLOGY OF THE NR2 GLUTAMATE BINDING SITE
  • 12.3 PHARMACOLOGY OF GLYCINE BINDING SITE ON NR1
  • 12.4 PHARMACOLOGY OF GLYCINE BINDING SITE ON NR3
  • 12.5 ALLOSTERIC MODULATORY SITES ON NMDA Receptors
  • 12.6 ZINC
  • 12.7 UNCOMPETITIVE ANTAGONISTS (CHANNEL BLOCKERS)
  • 12.8 CONCLUDING REMARKS
  • REFERENCES
• 13. Activation Mechanisms of the NMDA Receptor
  Marie L. Blanke and Antonius M.J. VanDongen.
  • 13.1 INTRODUCTION
  • 13.2 FUNCTION OF NMDA RECEPTORS
  • 13.3 STRUCTURE AND ACTIVATION
  • 13.4 CONCLUSIONS
  • REFERENCES
• 14. Presynaptic NMDA Receptors
  Ian C. Duguid and Trevor G. Smart.
  • 14.1 INTRODUCTION
  • 14.2 CRITERIA FOR DEFINING PRESYNAPTIC RECEPTORS
  • 14.3 LOCATIONS OF NMDA RECEPTORS AT SYNAPSES
  • 14.4 PHARMACOLOGY OF PRESYNAPTIC NMDA RECEPTORS
  • 14.5 SOURCES OF GLUTAMATE
  • 14.6 CONCLUSIONS
  • REFERENCES

Series editors: Sidney A Simon and Miguel AL Nicolelis

This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.