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Ion Channels DownUnder

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Contents

Contributors

Preface

Chapter One: GABAA Receptors and the Diversity in their Structure and Pharmacology

1. Introduction

2. Architecture of GABAARs

3. GABAAR Assembly: Selective Subunit Oligomerization

4. Multiple Subtypes, Locations, and Actions of GABAARs

5. Subunit Stoichiometry and Arrangement of GABAARs

6. Pharmacology of GABAARs

6.1. Orthosteric GABA Binding Sites

6.1.1. Extracellular β + α- Interfaces

6.1.2. Alternative GABA-Binding Interfaces?

6.2. Benzodiazepine Binding Sites

6.2.1. High-Affinity Site: Extracellular α + γ- Interface

6.2.2. Low-Affinity Benzodiazepine Binding Site(s)

6.3. Anesthetic Binding Sites in the TMD

6.3.1. Transmembrane β + α- Interfaces

6.3.2. Transmembrane α + β- and γ + β- Interfaces

6.3.3. Transmembrane β + β- Interface

6.3.4. The Promiscuity of Anesthetics Binding

6.4. Neurosteroid Binding Sites in the TMD

6.5. Variable Pharmacology of δ-Containing GABAARs

6.6. Natural Products of Plant Origin

7. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Two: Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future

1. Introduction

1.1. The ASIC Family

1.2. ASIC Distribution

1.3. ASIC Function and Structure

2. A Brief History of ASIC Pharmacology

3. The Current ASIC Tool Box

3.1. Nonselective Inhibitors of ASICs (Table1)

3.2. Nonselective Potentiators of ASICs (Table1)

3.3. Selective Modulators: ASIC1a Agonists/Potentiators (Table2)

3.4. Selective Modulators: ASIC1a Inhibitors (Table2)

3.5. Selective Modulators: ASIC1b and ASIC2a (Table2)

3.6. Selective Modulators: ASIC3 Agonists/Potentiators (Table2)

3.7. Selective Modulators: ASIC3 Inhibitors (Table2)

3.8. As yet Uncharacterized Modulators (Tested Only on Native ASIC Currents) (Table3)

4. The Future: What Do We Need and Where Will It Come From

5. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Three: Sodium Channels and Venom Peptide Pharmacology

1. Introduction

1.1. Nerve Excitability: An Historical Perspective

1.2. Voltage-Gated Sodium Channel Structure

1.3. Voltage-Gated Sodium Channel Gating

1.3.1. Channel Activation

1.3.2. Channel Inactivation

1.4. NaV Isoforms

1.4.1. NaV1.1

1.4.2. NaV1.2

1.4.3. NaV1.3

1.4.4. NaV1.4

1.4.5. NaV1.5

1.4.6. NaV1.6

1.4.7. NaV1.7

1.4.8. NaV1.8

1.4.9. NaV1.9

1.5. Pharmacology of Venom Peptides Acting at NaV Channels

1.5.1. Pore Blockers

1.5.1.1. Guanidinium Neurotoxins

1.5.1.2. μ-Conotoxins

1.5.2. Gating Modifiers

1.5.2.1. α-Scorpion Toxins

1.5.2.2. β-Scorpion Toxins

1.5.2.3. Sea Anemone Toxins

1.5.2.4. μ/β-Spider Toxins

1.5.2.5. μO-Conotoxins

1.5.2.6. μO§ GVIIJ

1.5.2.7. ι-Conotoxins

1.5.2.8. δ-Conotoxins and δ-Toxins From Spider Venom

1.5.2.9. Snake Toxins

2. Conclusion

2.1. Toxins as Tool Compounds: Insights and Future Directions

Conflict of Interest

Acknowledgments

References

Chapter Four: Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes

1. Introduction

2. Epithelial and Endothelial Cells

2.1. Colonic Epithelial Cells

2.2. Keratinocytes

2.3. Urothelial Cells

2.4. Vascular Endothelial Cells

3. Glial Cells

3.1. Astrocytes

3.2. Microglia

3.3. Satellite Glia

3.4. Müller Glia

4. Immune and Secretory Cells

4.1. Macrophages

4.2. T Cells

4.3. Chondrocytes

4.4. Myofibroblasts

5. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Five: Genetically Encoded Calcium Indicators as Probes to Assess the Role of Calcium Channels in Disease and for ...

1. Introduction

2. The Calcium Signal in Disease

3. The Calcium Signal as a Tool in Biomolecular Screening

4. Methods to Measure Cytosolic Calcium

4.1. Small Molecule Fluorescent Dyes for the Assessment of Ca2+ Signaling

4.2. GECIs for the Assessment of Ca2+ Signaling

4.2.1. Aequorin-Based GECIs

4.2.2. Förster Resonance Energy Transfer-Based GECIs

4.2.3. Single-Wavelength Fluorescent GECIs

5. New GECIs

6. Targeting GECIs

7. Application of GECIs in the Assessment of Calcium Homeostasis in Disease

8. GECIs and Biomolecular Screening

9. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Six: TRPV1 Channels in Immune Cells and Hematological Malignancies

1. Introduction

2. Overview of TRP Channels

3. TRPV1

3.1. Structure

3.2. TRPV1 Activation

3.3. Expression and Overexpression of TRPV1

4. TRPV1 Expression and Function in Immune Cells

4.1. Lymphocytes

4.2. Macrophages

4.3. Dendritic Cells

4.4. Neutrophils

5. TRPV1 in Hematological Malignancies

5.1. Leukemic Cell Lines

5.2. Adult T-Cell Leukemia

5.3. Multiple Myeloma

6. "Chili" and Vanilloids as Novel Chemotherapeutic Agents for Hematological Malignancies?

7. Conclusion

Conflict of Interest

References

Chapter Seven: Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to Structure

1. Introduction

2. High-Throughput Production of DRPs

3. High-Throughput Toxin Structure Determination

4. Structure of Channel:Toxin Complexes

4.1. KcsA:ChTX (Fig. 3A)

4.2. KvAPVSD:VSTx1 (Fig. 3B)

4.3. TRPV1:DkTx (Fig. 3C)

4.4. ASIC1a:PcTx1/MiTx (PcTx1 in Fig. 3D)

4.5. Summary

5. Conclusion

Conflict of Interest

Acknowledgments

References

Chapter Eight: Glycine Receptor Drug Discovery

1. Introduction

2. GlyR Subunits

3. GyRs and Disease

3.1. Hyperekplexia

3.2. Autism

3.3. Chronic Inflammatory Pain

3.4. Breathing Disorders

3.5. Temporal Lobe Epilepsy

3.6. Alcoholism

3.7. Motor Neuron Disease

4. GlyR Pharmacology

4.1. Competitive Antagonist: Strychnine

4.2. Allosteric Agonist: Ivermectin

4.3. Allosteric Modulators

4.4. Metals

4.5. Zn2+, a Potential Confound in GlyR Drug Discovery

5. Technologies for GlyR Drug Discovery

5.1. Fluorescence Assays

5.2. Electrophysiology

5.3. Artificial Synapses

5.4. Virtual Screening

6. Progress Toward Developing GlyR-Targeted Analgesics

7. Conclusion

Conflict of Interest Statement

Acknowledgments

References

Chapter Nine: Voltage-Gated Sodium Channel Pharmacology: Insights From Molecular Dynamics Simulations

1. Introduction

2. Molecular Dynamics Simulation Approaches

3. Sodium Channel-Toxin Interactions

3.1. Tetrodotoxin

3.2. Pore-Blocking Toxins

3.3. Voltage-Sensing Toxins

4. Sodium Channel-Small Molecule Interactions

4.1. Bilayer Partitioning

4.2. Route of Entry of Tonic Blocking Drugs

4.3. Location of Binding Sites

5. Conclusion

Acknowledgments

References

Chapter Ten: Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels

1. Introduction

2. RyR Overview

2.1. Ultrastructural Location

2.2. Protein Structure

3. Ion Channel Recording

4. EC Coupling

4.1. Transmission of Skeletal EC Coupling Signals

5. Pharmacology Arising From EC Coupling Studies

6. Regulation by Divalent Cations and CSQ

7. The FK506-Binding Proteins

8. CaM, Dantrolene, and S100A1

9. The Glutathione Transferase Structural Family

10. Oxidation, Phosphorylation, Doxorubicin, and Flecainide

11. Conclusion

Conflict of Interest

References

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