Front Cover

Pharmacology & Therapeutics of Constitutively Active Receptors

Copyright

Contents

Preface

Contributors

Chapter One: Constitutively Active Rhodopsin and Retinal Disease

1. Introduction

2. Rhodopsin Activity

2.1. Physiology of rhodopsin activity

2.2. Molecular switches that lock rhodopsin in an inactive state

3. Constitutive Activity in Rhodopsin that Causes Disease

3.1. Leber congenital amaurosis and vitamin A deficiency

3.1.1. Opsin: Active apoprotein

3.2. Congenital night blindness

3.2.1. G90D: Active dark state

3.2.2. T94I, A292E, and A295V: Active dark state

3.3. Retinitis pigmentosa

3.3.1. S186W and D190N: Thermal activation

3.3.2. G90V: Active dark state and thermal activation

3.3.3. K296E: Active apoprotein and stable arrestin interactions

4. How Constitutive Activity Can Cause Different Phenotypes

4.1. Different levels of activity as an underlying cause of different phenotypes

4.2. Do all constitutively active mutants adopt the same active-state conformation?

5. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Two: Constitutive Activity in Gonadotropin Receptors

1. Introduction

2. Naturally Occurring CAMs of the Gonadotropin Receptors

2.1. CAMs of the human LHCGR

2.2. CAMs of the human FSHR

3. Experimental Models of Gonadotropin Receptor CAMs

3.1. LHCGR CAMs and LH/hCG overexpressing mice

3.2. FSHR CAMs and FSHR overexpressing mice

4. Molecular Basis of Constitutive Activity in Gonadotropin Receptors

4.1. Mechanism of ligand-induced activation in gonadotropin receptors

4.2. Mechanisms leading to constitutive activity of gonadotropin receptors

5. Design of New Molecules for Controlling the Activity of Constitutively Active Gonadotropin Receptors

6. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Three: Constitutive Activities in the Thyrotropin Receptor: Regulation and Significance

1. Introduction

2. Constitutive Activity in the Thyrotropin Receptor

2.1. Properties related to Gs-mediated basal signaling activity

2.1.1. Structural determinants involved in regulation of basal signaling activity

2.1.2. Physiological aspects of basal signaling

2.2. Modulation of constitutive signaling activity

2.2.1. Constitutive signaling activity induced by mutations

2.2.2. Silencing of constitutive activity

2.2.2.1. Constitutive inactivation by mutations

2.2.2.2. Small-molecule ligands with inverse agonistic properties

2.2.2.3. Antibodies with inverse agonistic properties

3. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Four: Constitutive Activity in Cannabinoid Receptors

1. Introduction

2. Challenges in Proving Constitutive Receptor Activity

2.1. Demonstrating constitutive receptor activity requires the use of agonist, inverse agonist, and neutral antagonist

2.2. Constitutive active receptor versus constitutive agonist tone

2.3. Design issues in in vitro cell-based assay

3. Supporting Evidence for Constitutive Activity in Cannabinoid Receptors

4. Conclusion

Conflict of Interest

References

Chapter Five: Constitutive Activity in Melanocortin-4 Receptor: Biased Signaling of Inverse Agonists

1. Introduction

2. Constitutive Activity of MC4R in the Gs-cAMP Pathway

3. Constitutive Activity of MC4R in the ERK1/2 Pathway

4. In Vivo Relevance of the Constitutive Activity of the MC4R

5. Therapeutic Relevance of Inverse Agonism

6. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Six: Constitutive Activity in the Angiotensin II Type 1 Receptor: Discovery and Applications

1. Introduction

2. Discovering Constitutive Activity of AT1 Receptor

3. Mechanism of Constitutive Activation in AT1 Receptor

4. Inverse Agonists and Partial Agonists of AT1 Receptor

5. Constitutive Activity of AT1 Receptor In Vivo

6. Constitutive Activation of AT1 Receptor and Pathophysiology

6.1. Autoantibody activation

6.2. Stretch activation

7. CAM AT1 Receptors as Research Tools

7.1. Angiotensinergic activation of vascular endothelium

7.2. Low-renin hypertension model

7.3. Hypersympathetic vasomotor tone model

7.4. Renal proximal tubular AT1 receptor hyperactivity model

7.5. Adult cardiac myocyte-specific AT1 receptor hyperactivity induction model

8. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Seven: Constitutive Activities and Inverse Agonism in Dopamine Receptors

1. Introduction

2. Molecular Basis for the Constitutive Activities of D1-Class Receptors

3. Molecular Basis for the Constitutive Activities of D2-Class Receptors

4. Regulation of Constitutive Activities of D1-Class Receptors

4.1. Role of protein kinase C: Insights from pharmacological inhibitors

4.2. Role of lipid rafts

4.3. Role of desensitization and internalization

5. Physiological and Pathological Relevance of Constitutive Activity for Dopamine Receptors

5.1. Hypothalamic neurons and atrial natriuretic factor release

5.2. Hippocampus and learning and memory

5.3. Kidney and hypertension

5.4. Striatum and Huntington´s disease

5.5. Striatum and Parkinson´s disease

6. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Eight: Receptor Conformation and Constitutive Activity in CCR5 Chemokine Receptor Function and HIV Infection

1. Introduction

1.1. Physiological functions of the CCR5 chemokine receptor

1.2. Roles of the CCR5 chemokine receptor in inflammatory disease and HIV infection

1.3. Effects of CCR5 chemokine receptor deficiency

2. CCR5 Signaling Pathways and Evidence for Constitutive Activity of the Wild-Type CCR5 Chemokine Receptor

2.1. Chemokine-stimulated signaling

2.1.1. Evidence for membrane raft location of CCR5

2.1.2. Activation of Gi

2.1.3. Role of Gq/11

2.1.4. Activation of tyrosine kinases

2.1.5. Cytoskeleton and chemotaxis

2.1.6. Role of β-arrestin recruitment

2.2. Constitutive activity of the wild-type CCR5 receptor

2.3. HIV Env- and gp120-stimulated signaling

2.3.1. Calcium mobilization

2.3.2. Protein kinase activation

2.3.3. Secretion of proinflammatory cytokines and chemokines

2.3.4. Actin mobilization

2.3.5. Roles of membrane rafts and cholesterol in CCR5-mediated HIV entry

2.4. Physiological consequences of HIV activation of CCR5

2.4.1. Effects on HIV infection

2.4.2. Effects of CCR5 receptor density

2.4.3. Effects on AIDS pathogenesis

3. Role of CCR5 Chemokine Coreceptor Conformation in HIV Entry

3.1. Conformational heterogeneity of the CCR5 chemokine receptor

3.2. Constitutively active mutant CCR5 chemokine receptors and HIV infection

3.3. Inactive conformations of the CCR5 chemokine receptor mediate HIV entry

3.4. Mechanisms of action of CCR5 receptor-blocking agents and modes of HIV resistance

3.4.1. N-terminally modified chemokine analogs

3.4.2. Anti-CCR5 receptor antibodies

3.4.3. Small-molecule antagonists

4. Therapeutic Potential for CCR5 Chemokine Receptor Antagonists and Inverse Agonists

5. Conclusion

Conflict of Interest

References

Chapter Nine: Constitutively Active Chemokine CXC Receptors

1. Introduction

1.1. GPCR signaling pathways

1.2. CXC receptor members, ligands, cellular location, and disease involvement

1.3. 3D structure of CXC chemokine receptors

1.4. Constitutively active CXC chemokine receptors

2. Chemokine CXC Receptors

2.1. CXCR1

2.1.1. Clinical significance of CXCR1

2.1.2. Structural features of CXCR1 and regulation of CXCR1 signaling

2.1.3. Constitutively active CXCR1 mutation (V6.40A and V6.40N)

2.2. CXCR2

2.2.1. Clinical significance of CXCR2

2.2.2. Regulation of CXCR2 signaling

2.2.3. Constitutively active CXCR2 mutation (D138V)

2.3. CXCR3

2.3.1. Clinical significance of CXCR3

2.3.2. Structural features of CXCR3 and regulation of CXCR3 signaling

2.3.3. Constitutively active CXCR3 mutation (N3.35A, N3.35S, and T2.56P)

2.4. CXCR4

2.4.1. Clinical significance of CXCR4

2.4.2. Structural features of CXCR4 and regulation of CXCR4 signaling

2.4.3. Constitutively active CXCR4 mutation (N119S and N119A)

2.5. CXCR5

2.5.1. Clinical significance of CXCR5

2.6. CXCR6

2.6.1. Clinical significance of CXCR6

2.6.2. Structural features of CXCR6 and regulation of CXCR6 signaling

2.7. CXCR7

2.7.1. Clinical significance of CXCR4

2.7.2. CXCR4/CXCR7 heterodimer and biased arrestin signaling by CXCR7

2.8. KSHV-GPCR

2.8.1. Clinical significance of KSHV-GPCR

2.8.2. Structural features of KSHV-GPCR and regulation of KSHV-GPCR signaling

2.8.3. Constitutively active KSHV-GPCR

3. Conclusion

Conflict of Interest

References

Chapter Ten: Constitutive Activity of Bitter Taste Receptors (T2Rs)

1. Introduction

1.1. Taste sensory proteins

1.2. Bitter taste receptors

1.3. Expression and localization of T2Rs

2. Activation Mechanism of T2Rs

2.1. Role of highly conserved TM residues in T2R activation

2.2. Role of T2R-specific residues in agonist-induced activation

3. Constitutive Activity in GPCRs

3.1. Strategies used to identify CAMs in T2Rs

3.1.1. Measuring basal activity of the receptor

3.1.1.1. Calcium mobilization assay

3.1.1.2. Effect of receptor density on calcium mobilization

3.1.1.3. IP3 assay

3.1.2. Molecular modeling

3.2. T2R CAMs in the TM domain

3.3. T2R CAMs in ICL3

4. Role of CAMs in Discovery of Bitter Taste Blockers

5. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Eleven: Constitutive Activity of the Androgen Receptor

1. Introduction

2. Basic AR Functions

2.1. Ligands for AR activation

2.2. AR regulation and function in normal prostate gland

2.3. AR regulation and function in primary PCa and CRPC

2.4. Biochemical properties of different functional domains of AR

3. Modes of Constitutive and Hypersensitive Activity of Full-Length AR

3.1. AR activation by growth factor signaling pathways

3.2. AR activation by cytokines and inflammatory signaling

3.3. AR activation by coregulators

3.4. AR gene amplification and overexpression of AR protein

3.5. AR point mutations

4. Discovery of Constitutively Active AR Splice Variants

4.1. Identity and origin of AR-Vs

4.2. Constitutive transcriptional activity of AR-Vs

4.3. Genomic alteration in the generation of AR-Vs

4.4. Clinical relevance of AR-Vs

5. Mode of Action of Constitutive Active AR and AR-V in Gene Regulation

5.1. Pioneer factors in AR gene regulation

5.2. Coregulators interaction with AR-Vs

5.3. Gene targets of AR-Vs

6. Targeting Constitutive Activity of AR in PCa

6.1. Current status of drugs targeting endocrine regulation of AR

6.2. Therapeutic approaches to inhibit activity of the AR NH2-terminal domain

6.3. Biomarkers for monitoring persistent AR signaling

7. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Twelve: Sodium Channels, Cardiac Arrhythmia, and Therapeutic Strategy

1. Introduction

2. Structure and Physiological Function of Cardiac Na+ Channels

3. Cardiac Diseases Associated With Abnormal Na+ Channels

3.1. Long QT syndrome

3.1.1. Diagnosis of LQT3

3.1.2. Treatment of LQT3

3.2. Brugada syndrome

3.2.1. Diagnosis of BrS

3.2.2. Treatment of BrS

3.3. Other cardiac problems

3.4. Mutations of β-subunits and other regulatory proteins

4. Conclusion

Conflict of Interest

References

Chapter Thirteen: Constitutive Activity of the Acetylcholine-Activated Potassium Current IK,ACh in Cardiomyocytes

1. Introduction

2. Molecular Mechanisms of Constitutively Active IK,ACh

2.1. Receptor-independent activity of G proteins

2.1.1. Gαi-subunit as scavenger for Gβγ-subunits

2.1.2. Nucleoside diphosphate kinase B as potential activator of G proteins

2.2. Alterations within the IK,ACh channel complex

2.2.1. Regulation of the IK,ACh channels by PIP2 and Na+

2.2.2. Phosphorylation of the IK,ACh channel may contribute to constitutively active IK,ACh

3. Constitutively Active IK,ACh as Potential Therapeutic Target

4. Conclusion

Conflict of Interest

Acknowledgments

References

Index