Pharmacology of G Protein Coupled Receptors

Pharmacology of G Protein Coupled Receptors

1st Edition - September 8, 2011

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  • Editor: Richard R. Neubig
  • eBook ISBN: 9780123859532

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Description

G protein coupled receptors remain the most important class of therapeutic targets in medicine. In the last 5 years, tremendous advances have been made in our understanding of the structure and mechanism of this critical family of drug targets. The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors. It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones. In addition, emerging drug targets such as receptor families for fatty acids, carboxylic acids, lipid mediators, etc. are included. Final chapters cover novel mechanisms of signal regulation through PDZ domains and RGS proteins. This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists.

Key Features

  • The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors
  • It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones
  • This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists

Readership

Pharmacologists, immunologists, and biochemists

Table of Contents

  • Contributors

    Preface

    The Use of GPCR Structures in Drug Design

    Abbreviations

    I. Introduction

    II. Technology Developments Enabling GPCR Structure Determination

    III. GPCR Structures

    IV. GPCR Structures in Drug Discovery

    V. Conclusion

    Acknowledgments

    Allosteric Modulation of Metabotropic Glutamate Receptors

    Abbreviations

    I. Introduction

    II. Metabotropic Glutamate Receptors

    III. Pharmacological Profiles of mGlu Allosteric Modulators

    IV. Quantifying Allosteric Interactions

    V. Structural Determinants of mGlu Allosteric Modulator Binding

    VI. Functional Selectivity of mGlu Allosteric Modulation

    VII. Therapeutic Potential of mGlu Allosteric Modulators

    VIII. Conclusion

    Acknowledgments

    Refining Efficacy

    Abbreviations

    I. Introduction

    II. GPCRs as Conformational Ensembles

    III. The Pluridimensional Nature of GPCR Efficacy

    IV. Functionally Selective GPCR Agonism

    V. Functional Selectivity and Pharmaceutical Development

    VI. Functional Selectivity at the Parathyroid Hormone Receptor

    VII. Conclusion

    Acknowledgments

    Pharmacological Chaperones for Misfolded Gonadotropin-Releasing Hormone Receptors

    Abbreviations

    I. Introduction

    II. The Endoplasmic Reticulum Quality Control System

    III. Misfolding of GPCRs and Disease

    IV. Mutations in the Human GnRHR

    V. Rescue of Misfolded hGnRHR Mutants with Pharmacoperones

    VI. Mechanism of Action of Pharmacoperones

    VII. The Dominant-Negative Effect of hGnRHR Mutants and Receptor Rescue

    VIII. Conclusion

    Acknowledgments

    Regulation of Stability and Trafficking of Calcium-Sensing Receptors by Pharmacologic Chaperones

    Abbreviations

    I. Introduction

    II. CaSR: Physiological Contributions to Calcium Homeostasis

    III. CaSR and Disease

    IV. Posttranslational Mechanisms Controlling CaSR Abundance

    V. Pharmacologic Chaperone Contributions to Plasma Membrane Targeting of CaSR

    VI. Pharmacologic Chaperone Regulation of Organellar CaSR

    VII. Conclusion

    Acknowledgments

    Experimental Challenges to Targeting Poorly Characterized GPCRs

    Abbreviations

    I. Introduction

    II. Deorphanization of the Receptors for FFAs

    III. Uncovering the Pharmacology of FFA Receptors

    IV. Synthetic Ligands for FFA Receptors

    V. Therapeutic Potential for FFA Receptors

    VI. Conclusion

    Acknowledgments

    Biological and Pharmacological Roles of HCA Receptors

    Abbreviations

    I. Introduction

    II. Identification and Characterization of HCA Receptors

    III. Gene Structure and Tissue Distribution

    IV. Physiological and Pharmacological Roles of HCA Receptors

    V. Receptor Classification with Pharmacological Tools

    VI. Mutagenesis and Receptor-Modeling Studies

    VII. Signal Transduction and Receptor Desensitization

    VIII. Therapeutic Potential of HCA Receptor Ligands

    IX. Conclusion

    Acknowledgments

    Pharmacology, Signaling and Physiological Relevance of the G Protein-coupled Receptor 55

    I. Introduction

    II. The G Protein-Coupled Receptor 55

    III. Biological Relevance of GPR55

    IV. Conclusion

    Acknowledgments

    Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs

    Abbreviations

    I. Introduction

    II. PDZ Proteins

    III. GPCRs with Carboxy-Terminal PDZ Recognition Motifs

    IV. PDZ Protein Regulation of GPCR Signaling

    V. Conclusion

    Acknowledgments

    Regulator of G Protein Signaling Proteins as Drug Targets

    Abbreviations

    I. Introduction

    II. RGS Proteins Regulate Signaling via GPCRs

    III. Regulation of RGS Protein Function and Expression

    IV. Noncanonical Functions of RGS Proteins

    V. Biological Functions of RGS Proteins—Implications in Drug Discovery

    VI. Advances in RGS Protein Drug Discovery

    VII. The Future of Targeting RGS Proteins in Drug Discovery

    VIII. Conclusion

    GPCR-Interacting Proteins, Major Players of GPCR Function

    I. Introduction

    II. Biosynthesis and Cell Surface Targeting of GPCRs

    III. Modulation of GPCR Signaling

    IV. Endocytosis and Recycling of GPCRs

    V. Conclusion

    Acknowledgments

Product details

  • No. of pages: 408
  • Language: English
  • Copyright: © Academic Press 2011
  • Published: September 8, 2011
  • Imprint: Academic Press
  • eBook ISBN: 9780123859532

About the Serial Volume Editor

Richard R. Neubig

Richard R. Neubig

Dr. S. J. Enna received his B.A. degree (1965, Biology) from Rockhurst University, Kansas City, Missouri and both his M.S. (1967, Pharmacology) and Ph.D. (1970, Pharmacology) degrees from the University of Missouri-Kansas City. Postdoctoral training in pharmacology was completed at the University of Texas Southwestern Medical School in Dallas, at F. Hoffmann La Roche in Basel, Switzerland, and the Department of Pharmacology and Experimental Therapeutics at Johns Hopkins University School of Medicine in Baltimore. Dr. Enna spent 10 years on the faculty at the University of Texas Medical School at Houston in the Departments of Pharmacology and Neurobiology. While at the University of Texas Dr. Enna was also a consultant for ICI USA, Inc., Merck, Sharp and Dohme Research Laboratories, Bristol Myers Corporation, and Panlabs, Inc. From 1986 1990, Dr. Enna was Senior Vice President and Scientific Director of Nova Pharmaceutical Corporation in Baltimore, and Executive Vice President from 1990 1992. He is currently Associate Dean for Research and Graduate Education as well as Professor of Physiology and of Pharmacology at the University of Kansas Medical School. Dr. Enna served as chair of the Department of Pharmacology, Toxicology and Therapeutics at the University of Kansas Medical School from 1992 to 2003. Other previous academic appointments include Lecturer in the Department of Neuroscience at The Johns Hopkins University School of Medicine in Baltimore and Adjunct Professor of Pharmacology at Tulane University School of Medicine in New Orleans.

Dr. Enna served for six years as editor of The Journal of Pharmacology and Experimental Therapeutics, and is currently co-editor of Current Protocols in Pharmacology. He is also Editor-in-Chief of Biochemical Pharmacology, Executive Editor-in-Chief of Pharmacology and Therapeutics and Series Editor of Advances in Pharmacology. Besides his editorships, Dr. Enna serves on the editorial boards of Brain Research, Life Sciences and CNS Drug Reviews. He has been the recipient of Research Career Development Awards from the National Institute of Mental Health and the National Institute for Neurological, Communicative Disorders and Stoke. Other awards include the John Jacob Abel Award and the Torald Sollmann Award from the American Society for Pharmacology and Experimental Therapeutics, the Daniel H. Efron Award from the American College of Neuropsychopharmacology, and a PhARMA Foundation Excellence Award. In recent years he has been a member of the Scientific Advisory Council of Abbott Laboratories, has served on the Board of Directors of the Life Sciences Research Office, and on the Scientific Advisory Board of the National Alliance for Autism Research. He is currently a member of the Basic Pharmacology Advisory Committee of the PhARMA Foundation. Dr. Enna has held many elective offices in professional societies including the presidency of the American Society for Pharmacology and Experimental Therapeutics (ASPET). Since 2006 he has served as Secretary General of the International Union of Basic and Clinical Pharmacology (IUPHAR).

Dr. Enna's research interests include neuropharmacology, neurochemistry and neuropsychiatric disorders. He has made significant contributions in defining the pharmacological and biochemical properties of neurotransmitter receptors, in particular those for GABA. He has also conducted research into the effects of hormones on neurotransmitter receptor function and receptor responses to psychotherapeutics, the development of receptor antagonists for NMDA, cholinergic muscarinic and bradykinin receptors, and the identification of the cellular components of coincident signaling in brain. Dr. Enna's research is described in over 200 published research reports, reviews, and book chapters. He has authored or edited over three dozen books on topics ranging from neuropharmacology in general, to neurotransmitter receptors and GABA.

Affiliations and Expertise

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, USA

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