G Protein-Coupled Receptors as Drug Targets discusses an important biological process that has not yet been covered in such depth in any other existing books on GPCRs.

Features:

• Addresses in detail current models and concepts, to introduce medicinal chemists, physiologists, pharmacologists, and medical researchers into the advances in the understanding of GPCR activation and constitutive activity
• Provides an overview on methods of investigating constitutive GPCR activity
• Well illustrated by selected experimental data and schemes
• Covers general mechnisms, methodological approaches and cover selected important GPCR systems

Contents

Historical Background and Introduction

The Nature of Constitutive Activity and Inverse Agonism

• Historical Perspective
• Theoretical Basis of Inverse Agonism: Relevance of Receptor Type
• The Interaction of Systems with Ligands
• Inverse Agonism as a Phenotypic Behavior

Molecular Mechanisms of GPCR Activation

• GPCR Structure and Ligand Recognition
• Conformational Changes in the GPCR Activation Process
• Conversion to the Active Receptor State Involves Release of Stabilizing Intramolecular Interactions
• Kinetics of Agonist Binding and Receptor Activation
• GPCR Activation in an Oligomeric Context

Molecular and Cellular Determinants of GPCR Splice Variant Constitutive Activity

• Constitutive Activation of Second Messenger Production by C-Terminal Splice Variants of GPCRs
• Differential Constitutive Internalization of C-t GPCR Splice Variants

Naturally Occurring Constitutively Active Receptors: Physiological and Pharmacological Implications

• Wild-type Interspecies Homologues
• Wild-type Receptor Subtypes within a Given Species
• Wild-type Alternatively Spliced Receptors
• Polymorphisms in GPCRs
• GPCR Mutation-induced Disease

The Impact of G Proteins on Constitutive GPCR Activity

• The Contribution of G proteins to Constitutive Activity
• GPCR–G Protein Fusion Proteins

(Patho)physiological and Therapeutic Relevance of Constitutive Activity and Inverse Agonism at G Protein-Coupled Receptors

• Physiological Relevance of Constitutive Activity of GPCRs
• Constitutive Activity of GPCRs and Pathophysiology of Disease
• Physiological Relevance of Inverse Agonists
• Inverse Agonists as Drugs

Methodological Approaches

• Analysis of Constitutive GPCR Activity in Membranes and Intact Cells
• Measurement of Constitutive Activity of GPCRs in Intact Cells

Constitutive Activity of b-Adrenoceptors: Analysis in Membrane Systems

• Analysis of βAR/Gs Protein Coupling in Membranes
• Development of the Concept that βARs are Constitutively Active
• Probing Models of GPCR Activation with β2ARwt and β2ARCAM with Inverse Agonists
• Probing Models of GPCR Activation with β2ARwt and β2ARCAM and with Partial and Full Agonists
• Probing Models of GPCR Activation with β2ARwt and Purine Nucleotides
• Constitutive Activity of the β2AR Coupled to Various G?s Proteins
• Probing Models of GPCR Activation with β2AR Coupled to Various Classes of G proteins
• Comparison of the Constitutive Activities of the β1AR and the β2AR

Constitutive Activity of ?-Adrenoceptors: Analysis by Physiological Methods

• Constitutive Activity and Inverse Agonism: Definition and Detection
• β₁-Adrenoceptors
• β₂-Adrenoceptors
• Homo- and Heterodimerization of β1- and β2ARs

Constitutive Activity at the a1-Adrenoceptors: Past and Future Implications

• Theoretical and Experimental Approaches for Study of Constitutive GPCR Activity
• Constitutively Activating Mutations of the a1AR Subtypes
• A Putative Model of Receptor Activation for the a1BAR
• Constitutive Activity of Wild-type a1ARs and Inverse Agonism
• Receptor Regulation and Constitutive Activity of the a1ARs

Constitutive Activity of Muscarinic Acetylcholine Receptors: Implications for Receptor Activation and Physiological Relevance

• Constitutive Activity – Native Systems
• Constitutive Activity – Recombinant Systems
• Constitutive Activation by G Proteins
• Structure–Function Analysis of Receptor Activation
• Structure–Function Model for Activation

Constitutively Active Histamine Receptors

• The Histamine Receptors
• Assay Systems for Detection of Constitutive Activity of Histamine Receptors

Constitutively Active Serotonin Receptors

• 5-HT1A Receptor (5-HT1AR)
• 5-HT1B and 5-HT1D Receptors (5-HT1BR and 5-HT1DR)
• 5-HT2A Receptor (5-HT2AR)
• 5-HT2C Receptor (5-HT2CR)

Virally Encoded Constitutively Active Chemokine Receptors

• The Human Cytomegalovirus-encoded Chemokine Receptor Homologue pUS28
• The Human Kaposi’s Sarcoma Virus-encoded Chemokine Receptor KSHV-GPCR

Index

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