Voltage-gated Sodium Channels: Structure, Function and Channelopathies

Preface

Contents

Part I: Evolution of Voltage-Gated Sodium Channels

Evolutionary History of Voltage-Gated Sodium Channels

1 Introduction

2 Structural Outlines of Voltage-Gated Sodium Channels

3 Historical Origin of Voltage-Gated Sodium Channels and Their Related Proteins

4 Evolution of Bilaterians and Voltage-Gated Sodium Channel Proteins

5 Voltage-Gated Sodium Channels in Chordates

6 Evolution of NaV1 Channels in Vertebrates

7 Independent Gene Duplications of NaV1 in Teleosts and Amniotes

8 Concluding Remarks

References

Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits

1 Sodium Channel Basics

2 VGSC and Human Disease

3 ?-Subunit Homology from the Perspective of Primary Sequence

4 Evolutionary History of Beta-Subunits

5 Structural Features and Regions of Sequence Conservation

References

Part II: The Structural Basis of Sodium Channel Function

Structural and Functional Analysis of Sodium Channels Viewed from an Evolutionary Perspective

1 Introduction

2 The Voltage-Sensing Module

2.1 The Excitable Membrane and the Voltage Sensor

2.2 A Conserved Mechanism of Activation

3 The Selectivity Filter: From Symmetry to Asymmetry

4 Inactivation Evolved from Bacterial to Eukaryotic Sodium Channels

4.1 Slow Inactivation of Eukaryotic Sodium Channels

4.2 Studies of Slow Inactivation of Bacterial Sodium Channels

4.3 Evolution of Fast Inactivation in Eukaryotic Sodium Channels

5 Modulation of Sodium Channels by Their C-Terminal Tail

6 Conclusion

References

The Cardiac Sodium Channel and Its Protein Partners

1 Introduction

2 Specialized Membrane Domains in Cardiac Sarcolemma

2.1 Intercalated Disk

2.2 Lateral Membrane

2.2.1 Costamere

2.2.2 T-Tubule System

2.3 Localization of NaV1.5 Channels in Membrane Microdomains of Cardiac Myocytes

3 NAV1.5 Partners and Their Function in the Regulation of the Sodium Current

3.1 Cytoskeleton-Binding Proteins

3.2 GAP Junctional Proteins

3.3 Desmosomal Proteins

3.3.1 Plakophilin 2

3.3.2 Desmoglein 2

3.3.3 Plakoglobin

3.3.4 Desmoplakin

3.4 Dystrophin-Syntrophin Complex

3.5 Caveolins

3.6 MAGUK Proteins

3.6.1 ZO1

3.6.2 SAP97

3.6.3 CASK

4 Conclusion

References

Posttranslational Modification of Sodium Channels

1 Brief Overview of VGSCs

2 Posttranslational Modifications of VGSCs

2.1 Phosphorylation

2.2 Arginine Methylation

2.3 Glycosylation

2.4 Ubiquitination

2.5 SUMOylation

2.6 Palmitoylation

2.7 S-nitrosylation

2.8 ROS Modifications

3 Conclusions

References

Sodium Channel Trafficking

1 Introduction

2 Biosynthesis and Anterograde Transport

2.1 VGSC Processing and ER Quality Control

2.2 VGSC ER-to-Golgi Transport

2.3 VGSC Microtubule-Based Delivery

2.4 VGSC Oligomerization

2.5 VGSC Local Translation and Alternative Transports

3 Targeting and Subcellular Distribution of VGSC

4 VGSC Retrograde Transport

5 Trafficking Modulation in Physiopathology

6 Conclusion

References

pH Modulation of Voltage-Gated Sodium Channels

1 Introduction

2 Molecular Mechanisms of Proton Block

3 Proton Modulation of Channel Gating

4 Effects of Protons on Tissues

5 Acidosis and Disease

6 Conclusion

References

Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C

1 Introduction

2 Ionic Basis of Cardiac AP Waveform

3 Structural and Molecular Identity of Cardiac Nav1.5/INa Channel

3.1 Cardiac Nav1.5 Channel Subunits

3.2 Nav1.5 and Its Associated ?-Subunits

4 Protein Kinases and Modulation of Cardiac Nav1.5 Channels

4.1 Protein Phosphorylation and Cardiac Nav1.5 Channel Subunits

4.2 PKA-Dependent Phosphorylation and Cardiac Nav1.5 Channel Function

4.3 PKC-Dependent Phosphorylation and Cardiac Nav1.5 Function

5 Protein Kinases and Arrhythmias

5.1 Channelopathies of the Nav1.5 Channel Subunits

5.2 Kinase Regulation of Cardiac Nav1.5 in Long QT Syndrome 3

5.3 PKA and Channelopathies of the Nav1.5 Channel Complexes

5.4 PKC and Channelopathies of the Nav1.5 Channel Complexes

5.5 Kinase Regulation of Cardiac Nav1.5 in Brugada Syndrome (BrS)

6 Summary and Future Perspectives

References

Part III: Drugs and Toxins Interactions with Sodium Channels

Toxins That Affect Voltage-Gated Sodium Channels

1 Introduction

2 Toxins Binding to Site 1 of VGSCs

3 Toxins Binding to Site 2 of VGSCs

4 Toxins Binding to Site 3 of VGSCs

5 Toxins Binding to Site 4 of VGSCs

6 Toxins Binding to Site 5 of VGSCs

7 Toxins Binding to Site 6 of VGSCs

8 Conclusion

References

Mechanisms of Drug Binding to Voltage-Gated Sodium Channels

1 Introduction

2 Molecular Biology of Na+ Channels

3 Sodium Channelopathies

4 Structure and Function Relationships

5 Voltage-Dependent Gating of Na+ Channels

6 Mechanisms of Drug Binding and Channel Inhibition

7 Modulated Receptor Hypothesis

8 Guarded Receptor Hypothesis

9 Alternative Mechanisms of Drug Inhibition

10 Interaction Between Permeant Cations and Pore-Blocking Drugs

11 Drug Inhibition Is Voltage-Dependent

12 Modulation of Drug Binding by External Protons

13 Recovery from Drug Inhibition

14 Regulation of Drug Binding by Auxiliary ?-Subunits

15 Conclusion

References

Effects of Benzothiazolamines on Voltage-Gated Sodium Channels

1 Overview of Voltage-Gated Sodium Channels Pharmacology

2 Riluzole

2.1 Pharmacology of Riluzole

2.2 Molecular Effects of Riluzole on Sodium Channels

3 Lubeluzole

3.1 Pharmacology of Lubeluzole

3.2 Molecular Effects of Lubeluzole on Sodium Channels

4 Riluzole and Lubeluzole as Antimyotonic Drugs?

5 Conclusions

References

Structural Models of Ligand-Bound Sodium Channels

1 Structure of Sodium Channels

2 Homology Modeling and Ligand Docking

3 Inner Pore Blockers

4 Neurotoxins

5 Conclusion

References

Selective Ligands and Drug Discovery Targeting the Voltage-Gated Sodium Channel Nav1.7

1 Considerations for Selective, Therapeutic Targeting of Nav1.7

2 Introduction to Nav Channels

3 Nav Channel Structure, Biophysics, and Receptor Sites

4 Introduction to Nav1.7 Physiology and Channelopathies

5 Nav1.7 Receptor Sites: Potential for Selective Targeting

6 Inner Vestibule Nav Channel Antagonists

7 Extracellular Vestibule Selectivity Filter Blockers

8 Voltage-Sensor Targeting: Gating Modifying Peptides

8.1 The Pn3a Peptide

8.2 ProTx2 and Derivatives

9 Trapping VSD4: Identification of the Subtype Selective Aryl Sulfonamides

10 Opportunities and Challenges in Nav1.7 Drug Discovery

10.1 Pharmacokinetic Properties

10.2 State-Dependence of Inhibition

10.3 Efficiency of In Vivo Target Engagement

10.4 Toxicity Considerations

11 Perspective and Future Outlook

References

Part IV: Pathophysiology of Sodium Channels

Sodium Channelopathies of Skeletal Muscle

1 The Na+ Channel of Skeletal Muscle

2 Clinical Phenotypes Associated with NaV1.4 Mutations

3 Overview of NaV1.4 Mutations

3.1 Gain-of-Function Mutations Cause Myotonia and Hyperkalemic Periodic Paralysis

3.1.1 Gating Defects in Myotonia and HyperPP

3.1.2 Pathophysiologic Mechanism of Myotonia and HyperPP

3.2 Anomalous Gating Pore Conduction in Hypokalemic Periodic Paralysis

3.2.1 Gating Pore Current in HypoPP Mutant Channels

3.2.2 Pathophysiologic Mechanism for HypoPP

3.3 Loss-of-Function Mutations: Myasthenia and Congenital Myopathy

3.3.1 Loss-of-Function Defects in Myasthenia and Myopathy

3.3.2 Pathophysiologic Mechanism of Myasthenic Weakness

References

Cardiac Arrhythmias Related to Sodium Channel Dysfunction

1 Introduction

2 SCN5A Mutations and Cardiac Arrhythmias

2.1 Rare SCN5A Exonic Variants

2.1.1 Long QT Syndrome (LQTS)

2.1.2 J-Wave Syndromes: Brugada and Early Repolarization Syndrome

2.1.3 Progressive Cardiac Conduction Disease (PCCD or Lenegre-Lev Disease)

2.1.4 Sick Sinus Syndrome (SSS)

2.1.5 Sudden Infant Death Syndrome (SIDS)

2.1.6 Atrial Fibrillation (AF)

2.1.7 Dilated Cardiomyopathy Disease (DCM)

2.1.8 Multifocal Ectopic Purkinje-Related Premature Contractions (MEPPC)

2.1.9 Overlap Syndromes

2.2 Common SCN5A EXONIC Variants

2.3 Common SCN5A Intronic Variants (SCN5A-SCN10A Interaction/Regulation)

3 Summary

References

Translational Model Systems for Complex Sodium Channel Pathophysiology in Pain

1 Congenital Pain Syndromes

1.1 Nav1.7 in Human Pain Syndromes

1.2 Nav1.8 and Nav1.9 in Pain (Less) Disorders

2 Translation from Dish to Rodent to Human

2.1 Heterologous Expression of Human Proteins

2.2 Human DRGs as a Model System

2.3 Human Microneurography

2.4 Human Pluripotent Stem Cell-Derived Nociceptors

3 Concluding Remarks

References

Gating Pore Currents in Sodium Channels

1 Part I: Voltage Sensing Domains and Gating Pores

1.1 The Voltage Sensor Domain

1.2 Gating Pores

1.3 Gating Pore Currents and Action Potentials

2 Part II: Gating Pores and Sodium Channelopathies

2.1 Skeletal Muscle Channelopathies: Mutation-Based Phenotype and Gating Defects

2.2 Hypokalemic Periodic Paralysis: Role of the Omega Current

2.3 Cardiac Channelopathies

2.4 Cardiac Channelopathies: Role of the Omega Current

2.5 Pharmacology of Sodium Channelopathies Associated with Gating Pore Current

3 Part III: Computational Approaches to Investigate Gating Pore Current

3.1 Action Potential Modeling

3.2 All-Atom Molecular Dynamics

References

Calculating the Consequences of Left-Shifted Nav Channel Activity in Sick Excitable Cells

1 Introduction

2 Experimental Basis of the Nav-CLS Model

3 The Coupled Left-Shift Model (CLS)

4 CLS in a Node with Two Nav Populations (Intact and Damaged) and No Pumps

5 Excitability and CLS Damage in a Node with Pumps

6 CLS-Induced Pathological Activity for Realistically Complex Membrane Damage

7 Dynamical Analysis of Ectopic Bursting

8 Saltatory Propagation in Axons with Mildly Damaged Nodes

9 Sick Excitable Cells and Nav-CLS in Other Modeling Contexts

10 The CLS Model Within NEURON, the Simulation Environment

11 Conclusion

References

Voltage-Gated Sodium Channel ? Subunits and Their Related Diseases

1 The Basics of the Voltage-Gated Sodium Channel ? Subunits

1.1 Modulation of the Ion Channel Pore by ? Subunits

1.2 The ? Subunits as Cell Adhesion Molecules

2 The Role of ? Subunits in Pathophysiology

2.1 Cancer

2.2 Cardiac Arrhythmia

2.3 Epilepsy

2.4 Neurodegenerative Disorders

2.5 Neuropathic Pain

2.6 Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Death in Epilepsy (SUDEP)

3 Conclusion

References