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

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