Pharmacology of G Protein Coupled Receptors

1st Edition, Volume 62 - September 8, 2011
Editor: S. J. Enna
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 3 8 5 9 5 2 - 5
eBook ISBN:
9 7 8 - 0 - 1 2 - 3 8 5 9 5 3 - 2

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 th… Read more

Pharmacology of G Protein Coupled Receptors

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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.

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

S. J. Enna

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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Pharmacology of G Protein Coupled Receptors

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S. J. Enna