The Pharmacology of Functional, Biochemical, and Recombinant Receptor Systems,9783540661245

The Pharmacology of Functional, Biochemical, and Recombinant Receptor Systems

by ; ; ; ; ;
ISBN13: 9783540661245
ISBN10: 3540661247
Format: Hardcover
Pub. Date: 2000-09-01
Publisher(s): Springer Nature
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Summary

The technology of drug testing is rapidly advancing. This book brings together world renowned experts in the fields of pharmacology and physiology united with the common theme of describing methods, theoretical concepts and in vitro systems used to study drug receptor mechanisms and the action of drugs on receptors. The first section deals with the physiology and pharmacology of integrated natural systems, the second with the new theoretical ideas used to model receptor systems (i.e. the nature of efficacy, receptor activation) and the third with the new in vitro systems available for the study of receptors and drugs. The latest ideas regarding receptor theory are critically evaluated and presented to the reader.

Table of Contents

Introduction: Bioassays - Past Uses and Future Potential 1(15)
J.W. Black
Section I: Classical Pharmacology and Isolated Tissue Systems
Human Vascular Receptors in Disease: Pharmacodynamic Analyses in Isolated Tissue
15(36)
J.A. Angus
Introduction
15(1)
Receptors Mediating Coronary Artery Contraction: Role in Variant Angina
16(12)
Large Coronary Arteries
16(1)
Ergometrine
16(1)
5-HT and Endothelium-Derived Relaxing Factor
16(5)
Small Resistance Arteries
21(6)
Summary and Future Work
27(1)
Vascular Reactivity in Human Primary Hypertension and Congestive Heart Failure
28(9)
The Technique, Function and Structure
28(1)
Remodelling
29(2)
Endothelial Dysfunction
31(2)
Forearm Veins in Primary Hypertension
33(1)
Chronic Heart Failure
34(3)
Pharmacology of Vascular Conduits for Coronary-Bypass Graft Surgery
37(4)
Introduction
37(1)
Internal Mammary Artery
38(3)
Saphenous Vein
41(1)
Human Vascular-to-Cardiac Tissue Selectivity of L-and T-Type VOCC Antagonists
41(10)
References
47(4)
Problems in Assigning Mechanisms: Reconciling the Molecular and Functional Pathways in α-Adrenoceptor-Mediated Vasoconstriction
51(22)
M.J. Lew
Introduction
51(1)
Coupling Mechanisms at the Molecular and Cellular Levels
52(4)
α1-Adrenoceptors
52(2)
α2-Adrenoceptors
54(2)
Coupling Mechanisms in the Intact Animal
56(3)
Reconciliation
59(2)
Myogenic Activation
61(1)
Autocrine and Paracrine Activation
62(2)
Functional Antagonism
64(2)
Adenylate Cyclase and α2-Adrenoceptors
66(2)
Conclusions
68(5)
References
69(4)
Gs Protein-Coupled Receptors in Human Heart
73(46)
A.J. Kaumann
Introduction
73(1)
Receptor Subtypes
73(1)
β-Adrenoceptor Subtypes
74(6)
Comparison of β1- and β2-Adrenoceptors
74(1)
Localisation
74(1)
Function of β1- and β2-Adrenoceptors
74(1)
Selective Coupling of β2-Adrenoceptors
75(5)
Is There a Functional role for Cardiac β3-Adrenoceptors?
80(2)
Evidence Against Cardiostimulation
80(1)
Evidence for Cardiostimulation
81(1)
Evidence for Cardiodepression
81(1)
Evidence Against Cardiodepression
82(1)
Cardiostimulant Effect Through the Putative β4-Adrenoceptor
82(8)
Non-Conventional Partial Agonists
82(2)
The Putative β4-Adrenoceptor Resembles - But Is Distinct from - the β3-Adrenoceptor
84(3)
Which Endogenous Agonist for the Putative β4-Adrenoceptor?
87(1)
The Putative β4-Adrenoceptor is a Special State of the β1-Adrenoceptor
88(2)
5-HT4 Receptors
90(5)
Coupling to a cAMP Pathway
90(1)
5-HT4-like Receptors
91(4)
Cross-Talk Between Cardiac Gs-Coupled Receptors, as Revealed by Chronic Blockade of β1-Adrenoceptors
95(6)
Physiological, Pathophysiological and Therapeutic Relevance
101(6)
β1-and β2-Adrenoceptors
101(4)
Putative β4-Adrenoceptors
105(1)
5-HT4 Receptors
105(2)
Epilogue
107(12)
References
108(11)
Section II: New Theoretical Concepts and Molecular Mechanisms of Receptor Function
Kinetic Modeling Approaches to Understanding Ligand Efficacy
119(28)
J.J. Linderman
Introduction
119(1)
Background
120(6)
Efficacy
120(1)
Modeling
121(1)
Equilibrium, Steady State, and Kinetic Models
122(1)
Diffusion-Versus Reaction-Controlled Events
123(1)
Model Structures and Dose-Response Curves
124(2)
Parameters Contributing to Ligand Efficacy
126(17)
The Lifetime of the Individual Receptor-Ligand Complex (1/kr)
126(5)
The Receptor Desensitization Rate Constant kx
131(3)
The Ligand Binding and Dissociation Rate Constants at Endosomal pH
134(5)
Rate Constants in a Ternary Complex Model
139(4)
Concluding Remarks
143(4)
References
144(3)
The Evolution of Drug-Receptor Models: The Cubic Ternary-Complex Model for G Protein-Coupled Receptors
147(20)
T. Kenakin
P. Morgan
M. Lutz
J. Weiss
Receptor Models
147(1)
The Ternary Complex Model of Receptor Function
148(1)
Two-State Theory
149(2)
The Extended Ternary Complex Model
151(1)
The CTC Model
152(3)
General Application of the Cubic Model
155(8)
Evidence for the AriG Complex
158(5)
Conclusion
163(4)
References
163(4)
Inverse Agonism
167(16)
R. Bond
G. Milligan
M. Bouvier
Background
167(1)
Overexpression, Spontaneous Activity and Inverse Agonism
168(5)
Mutations and Diseases of Spontaneous Receptor Activity
173(1)
Modulation of Receptor Function by Agonists and Inverse Agonists
174(3)
Models
177(1)
Summary and Conclusions
178(5)
References
178(5)
Efficacy: Molecular Mechanisms and Operational Methods of Measurement. A New Algorithm for the Prediction of Side Effects
183(34)
T. Kenakin
Introduction
183(1)
The Molecular Nature of Efficacy
183(3)
Positive and Negative Efficacy
186(2)
The Operational Measurement of Relative Efficacy
188(13)
Binding Studies
188(1)
Guanosine Triphosphate γS Shift
188(3)
High-Affinity Selection Binding
191(1)
Function
192(3)
The Method of Furchgott
195(1)
The Method of Stephenson
196(1)
Comparison of Relative Maximal Responses
197(4)
Limitations of Agonist Potency Ratios
201(3)
Why Measure the Relative Efficacies of Agonists?
204(2)
A Simple Algorithm for the Prediction of Agonist Side Effects Using Efficacy and Affinity Estimates
206(9)
Therapeutic Versus Secondary Agonism: Side Effect Versus Coupling Constant Profiles
208(2)
Algorithm for Calculation of Relative β50
210(2)
Application of the Algorithm to β3-Adrenoceptor Agonists
212(2)
Limitations of the Algorithm
214(1)
Conclusions
215(2)
References
215(2)
A Look at Receptor Efficacy. From the Signalling Network of the Cell to the Intramolecular Motion of the Receptor
217(44)
H.O. Onaran
A. Scheer
S. Cotecchia
T. Costa
Introduction
217(1)
Biological Receptors and the Dualism of Affinity and Efficacy
217(4)
Signal Transfer and Conformational Change in Membrane Receptor
217(1)
The Distinction Between Affinity and Efficacy
218(1)
Generality of the Concept of Efficacy in Functional Proteins
219(1)
Asking the Questions
219(1)
Two Flavours in the Definition of Efficacy: Biological and Molecular
220(1)
Biological Definitions of Efficacy
221(6)
The Nature of Signal Strength
221(1)
Stimulus-Response Relationships
222(1)
The Scale of Agonism and Antagonism
223(2)
Steps of Signal Transduction and the Indeterminacy of Stimulus-Response Relationships
225(2)
Molecular Definitions of Efficacy
227(11)
A Molecular Link Between Affinity and Efficacy
227(1)
Allosteric Equilibrium, Free-Energy Coupling, and Thermodynamic Definitions of Efficacy
227(4)
Linkage Between Macroscopic Perturbations in the Receptor
231(2)
Functional and Physical States in Proteins
233(2)
Microscopic Interpretation of Allosteric Equilibrium
235(3)
A Stochastic Model of Molecular Efficacy
238(23)
Protein Motion and Fluctuations in Its Conformational Space
238(1)
Probability Distribution of Microscopic States and Derivation of Macroscopic Constants
238(3)
Probabilistic Interpretation of Ligand Efficacy
241(3)
Relationship Between Physical States and Biological Function
244(1)
Relationship Between Efficacy and Fluorescence Changes in β2-Adrenoceptors
244(4)
Correlated Macroscopic Changes in Constitutively Active Adrenoceptors
248(6)
References
254(7)
Mechanisms of Non-Competitive Antagonism and Co-Agonism
261(22)
D.G. Trist
M. Corsi
Non-Competitive Antagonism
261(6)
Definition
261(1)
Analysis of the Effect of Non-Competitive Antagonists
261(6)
Co-Agonism
267(12)
Theory as Applied to the Glutamate NMDA Receptor
267(1)
Evidence for Co-Agonism
267(1)
The Theory of Co-Agonism
268(3)
The Effect of a Competitive Antagonist on the Response of Co-Agonism
271(2)
The Effect of a Non-Competitive Antagonist on the Response of Co-Agonists
273(1)
Experimental Data Supporting the Concept of Co-Agonism and Its Antagonism
274(1)
Recombinant Experiments
274(2)
Tissue Experiments
276(2)
Implications of Co-Agonism
278(1)
General Observations
279(4)
References
280(3)
Mechanisms of Receptor Activation and the Relationship to Receptor Structure
283(30)
D.M. Perez
S.S. Karnik
Introduction
283(1)
Common GPCR Structure/Function
283(3)
Rhodopsin and bR Activation: Light as the Ligand
286(5)
Direct Structural Information
287(1)
The Activation Mechanism
288(1)
How Retinal Binds
288(1)
Salt-Bridge Constraining Factor: Movement of TM3 and TM6
289(2)
AR Activation: Small Organics as Ligands
291(7)
Important Binding Contacts of the Endogenous Ligands
291(2)
Insights on How Epinephrine Activates
293(1)
Release of Constraining Factors
293(1)
Evidence for a Salt-Bridge as a Constraint: Movement of TM3 and TM7
294(2)
Evidence for Multiple Activation States or Mechanisms
296(1)
Evidence for Additional Constraining Factors: Movement of TM5 and TM6
296(2)
Angiotensin-Receptor Activation: Peptides as Ligands
298(4)
Peptide-Hormone GPCRs: How the Peptide Binds
298(1)
The Ang-II Receptor
298(1)
How AngII Peptides and Non-Peptides Bind
299(1)
Insights into AngII Activation
300(1)
Role of His256 in TM6
300(1)
Release of Constraining Factors: Role of TM3
300(2)
The Ties that Bind: Concluding Remarks
302(11)
Conservation of Critical Binding Contacts and Resulting Helical Movements
302(1)
Conservation of Switches that Control Attainment of the Active State(s)
302(2)
References
304(9)
Section III: New Technologies for the Study of Drug Receptor Interaction
The Assembly of Recombinant Signalling Systems and Their Use in Investigating Signaling Dynamics
313(22)
S.M. Lanier
Introduction
313(1)
Assembly of Recombinant Signaling Systems
314(4)
Stable Transfection
314(2)
Transient Expression Systems
316(2)
Drug-Receptor Interactions in Recombinant Signaling Systems
318(10)
Cell-Type-Specific Signaling Events
318(5)
Influence of Accessory Proteins
323(5)
Perspective
328(7)
References
328(7)
Insect Cell Systems to Study the Communication of Mammalian Receptors and G Proteins
335(28)
R.T. Windh
A.J. Barr
D.R. Manning
Introduction
335(3)
Selectivity of Receptor-G Protein Interactions
335(1)
Effector Modulation as a Measure of G Protein Activity
336(1)
Direct Measures of G Protein Activity
337(1)
Insect Cell Expression Systems
338(7)
Expression of Receptors in Insect Cell Lines
338(4)
Interaction of Receptors with Endogenous G Proteins and Effectors
342(1)
Quantitation of Coupling Using Radioligand Binding
343(2)
Reconstitution of Mammalian Receptors and G Proteins: Reconstituted Properties of Ligand Binding
345(5)
Influence of Heterotrimeric G Proteins on Binding of Agonists
346(2)
Influence of Individual G Protein Subunits on Binding of Agonists
348(1)
Characterization of Inverse Agonism
349(1)
Reconstitution of Mammalian Receptors and G Proteins: G Protein Activation
350(6)
Activation Following Co-Expression of Receptor and G Protein
350(4)
Activation Following Addition of Purified G Protein to Membranes
354(1)
Limitations and Technical Considerations
355(1)
Conclusions
356(1)
References
356(7)
Altering the Relative Stoichiometry of Receptors, G Proteins and Effectors: Effects on Agonist Function
363(28)
G. Milligan
Introduction
363(4)
Background
363(1)
Systems to Modulate GPCR--G Protein-Effector Stoichiometries
364(1)
Cellular Distribution of Elements of G Protein-Coupled Signaling Cascades
365(2)
GPCR-G Protein Fusion Proteins. A Novel Means to Restrict and Define the Stoichiometry of Expression of a GPCR and a G Protein α Subunit
367(3)
G Protein-Coupled Receptors
370(6)
Gsα
376(4)
Effector Enzymes: Adenylyl Cyclase
380(3)
Conclusions
383(8)
References
383(8)
The Study of Drug-Receptor Interaction Using Reporter Gene Systems in Mammalian Cells
391(24)
D.M. Ignar
S. Rees
Reporter Systems
391(10)
What is a Reporter Gene System?
391(1)
Detection Methods
391(1)
Enzymatic
391(2)
Non-Enzymatic
393(1)
Measurement of Intracellular Signaling
393(1)
Inducible Reporter Genes
393(1)
Responsive Promoters
393(2)
Chimeric Transcription Factors
395(2)
Reporter Proteins
397(3)
Transient Versus Stable Expression of Reporter Genes
400(1)
Transient Expression
400(1)
Stable Expression
400(1)
Use of Reporter Gene Systems in Pharmacology
401(14)
Drug Discovery
401(1)
Receptor Pharmacology
401(1)
Use of Reporter Gene Assays to Assess Receptor Agonism
402(1)
6CRE-Luciferase as a Reporter for Gαs-Coupled Receptor Signaling
402(1)
Aequorin as a Reporter for Gαaq11-Coupled Receptor Signaling
402(3)
The Use of a Ga14/Elk-1 Chimera to Report Opioid-Receptor-Like Receptor-1 Activation of MAPK
405(1)
Use of Reporter Gene Assays to Evaluate Receptor Antagonism
405(1)
Simultaneous Detection of Multiple Signals
405(1)
Dual Reporter Assays
405(2)
Combination of Reporter Assays with Other Assay Types
407(2)
Measurement of constitutive Activity
409(2)
Measurement of Efficacy
411(1)
Assessment of New Signaling Pathways
411(1)
References
412(3)
Melanophore Recombinant Receptor Systems
415(26)
C.K. Jayawickreme
M.R. Lerner
Introduction
415(2)
Cellular Signaling in Melanophores
417(6)
Signaling Pathways
417(2)
Endogenous Receptor Signaling
419(2)
Melatonin 1c Receptor
421(1)
α-Melanocyte Stimulating Hormone (MSH) Receptor
421(1)
Endothelin-C Receptor
422(1)
Serotonin Receptor
422(1)
β-Adrenoreceptor
422(1)
VIP Receptor
423(1)
Melanophore Assay Technology
423(6)
Cell Culture and Related Techniques
423(1)
Preparation of Cultures of Melanophore
423(1)
Continuous Culturing of Xenopus laevis Melanophores
424(1)
Receptor Expression
424(1)
Preparation of Stable Melanophore Lines Expressing Exogenous Receptors
425(1)
Signal Detection
425(1)
Transmittance Reading
425(1)
Digital Imaging
426(1)
Screening Formats
427(1)
Microtiter Well Format
427(1)
Lawn Format
428(1)
Receptor Cloning and Mutagenesis Studies
428(1)
Receptor Studies and Applications
429(6)
Characterization of Novel GPCRs
431(1)
Lawn Format Screen System
432(1)
Single Transmembrane Receptors
433(1)
Receptor-Ligand Interaction Studies
434(1)
Summary
435(6)
References
435(6)
Subject Index 441

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