Voltage-gated Sodium Channels: Structure, Function and Channelopathies (eBook)

Dr. Mohamed Chahine is a Professor at the Department of Medicine of Université Laval and Head of the Laboratory of Cellular Electrophysiology at the CERVO Brain Research Center of the Institut universitaire en santé mentale de Québec. He has published over 160 articles in refereed journals as well as several book chapters in the field of voltage-gated Na+ channels and related diseases. Dr. Chahine has served or is currently serving on various committees of the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. He is associate editor of Frontiers Journal and editor of Scientific Reports. He is a member of the editorial boards of the Canadian Journal of Cardiology (Canada), the World Journal of Cardiology (China), the Journal of Cardiovascular Research (USA), Advances in Bioscience and Biotechnology (USA), and the Journal of Cardiology and Therapy (Hong Kong). He has also organized several national and International symposia and workshops on the role of ion channels in disease. Dr. Chahine has been invited to present his research at several national and international conferences and academic institutions.

Preface 6
Contents 9
Part I: Evolution of Voltage-Gated Sodium Channels 11
Evolutionary History of Voltage-Gated Sodium Channels 12
1 Introduction 13
2 Structural Outlines of Voltage-Gated Sodium Channels 14
3 Historical Origin of Voltage-Gated Sodium Channels and Their Related Proteins 17
4 Evolution of Bilaterians and Voltage-Gated Sodium Channel Proteins 21
5 Voltage-Gated Sodium Channels in Chordates 25
6 Evolution of NaV1 Channels in Vertebrates 29
7 Independent Gene Duplications of NaV1 in Teleosts and Amniotes 32
8 Concluding Remarks 35
References 35
Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits 42
1 Sodium Channel Basics 43
2 VGSC and Human Disease 45
3 ?-Subunit Homology from the Perspective of Primary Sequence 46
4 Evolutionary History of Beta-Subunits 47
5 Structural Features and Regions of Sequence Conservation 50
References 54
Part II: The Structural Basis of Sodium Channel Function 11
Structural and Functional Analysis of Sodium Channels Viewed from an Evolutionary Perspective 60
1 Introduction 61
2 The Voltage-Sensing Module 62
2.1 The Excitable Membrane and the Voltage Sensor 62
2.2 A Conserved Mechanism of Activation 64
3 The Selectivity Filter: From Symmetry to Asymmetry 66
4 Inactivation Evolved from Bacterial to Eukaryotic Sodium Channels 69
4.1 Slow Inactivation of Eukaryotic Sodium Channels 69
4.2 Studies of Slow Inactivation of Bacterial Sodium Channels 70
4.3 Evolution of Fast Inactivation in Eukaryotic Sodium Channels 71
5 Modulation of Sodium Channels by Their C-Terminal Tail 72
6 Conclusion 74
References 74
The Cardiac Sodium Channel and Its Protein Partners 80
1 Introduction 81
2 Specialized Membrane Domains in Cardiac Sarcolemma 82
2.1 Intercalated Disk 83
2.2 Lateral Membrane 84
2.2.1 Costamere 84
2.2.2 T-Tubule System 85
2.3 Localization of NaV1.5 Channels in Membrane Microdomains of Cardiac Myocytes 85
3 NAV1.5 Partners and Their Function in the Regulation of the Sodium Current 86
3.1 Cytoskeleton-Binding Proteins 87
3.2 GAP Junctional Proteins 88
3.3 Desmosomal Proteins 89
3.3.1 Plakophilin 2 89
3.3.2 Desmoglein 2 91
3.3.3 Plakoglobin 92
3.3.4 Desmoplakin 92
3.4 Dystrophin-Syntrophin Complex 92
3.5 Caveolins 94
3.6 MAGUK Proteins 95
3.6.1 ZO1 95
3.6.2 SAP97 96
3.6.3 CASK 97
4 Conclusion 98
References 99
Posttranslational Modification of Sodium Channels 107
1 Brief Overview of VGSCs 108
2 Posttranslational Modifications of VGSCs 111
2.1 Phosphorylation 112
2.2 Arginine Methylation 114
2.3 Glycosylation 114
2.4 Ubiquitination 115
2.5 SUMOylation 116
2.6 Palmitoylation 116
2.7 S-nitrosylation 121
2.8 ROS Modifications 123
3 Conclusions 124
References 125
Sodium Channel Trafficking 131
1 Introduction 132
2 Biosynthesis and Anterograde Transport 134
2.1 VGSC Processing and ER Quality Control 134
2.2 VGSC ER-to-Golgi Transport 134
2.3 VGSC Microtubule-Based Delivery 136
2.4 VGSC Oligomerization 136
2.5 VGSC Local Translation and Alternative Transports 137
3 Targeting and Subcellular Distribution of VGSC 138
4 VGSC Retrograde Transport 140
5 Trafficking Modulation in Physiopathology 141
6 Conclusion 143
References 144
pH Modulation of Voltage-Gated Sodium Channels 152
1 Introduction 153
2 Molecular Mechanisms of Proton Block 155
3 Proton Modulation of Channel Gating 156
4 Effects of Protons on Tissues 157
5 Acidosis and Disease 159
6 Conclusion 161
References 161
Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C 166
1 Introduction 167
2 Ionic Basis of Cardiac AP Waveform 169
3 Structural and Molecular Identity of Cardiac Nav1.5/INa Channel 169
3.1 Cardiac Nav1.5 Channel Subunits 169
3.2 Nav1.5 and Its Associated ?-Subunits 170
4 Protein Kinases and Modulation of Cardiac Nav1.5 Channels 172
4.1 Protein Phosphorylation and Cardiac Nav1.5 Channel Subunits 172
4.2 PKA-Dependent Phosphorylation and Cardiac Nav1.5 Channel Function 172
4.3 PKC-Dependent Phosphorylation and Cardiac Nav1.5 Function 176
5 Protein Kinases and Arrhythmias 178
5.1 Channelopathies of the Nav1.5 Channel Subunits 178
5.2 Kinase Regulation of Cardiac Nav1.5 in Long QT Syndrome 3 179
5.3 PKA and Channelopathies of the Nav1.5 Channel Complexes 179
5.4 PKC and Channelopathies of the Nav1.5 Channel Complexes 180
5.5 Kinase Regulation of Cardiac Nav1.5 in Brugada Syndrome (BrS) 182
6 Summary and Future Perspectives 182
References 184
Part III: Drugs and Toxins Interactions with Sodium Channels 190
Toxins That Affect Voltage-Gated Sodium Channels 191
1 Introduction 192
2 Toxins Binding to Site 1 of VGSCs 192
3 Toxins Binding to Site 2 of VGSCs 194
4 Toxins Binding to Site 3 of VGSCs 196
5 Toxins Binding to Site 4 of VGSCs 197
6 Toxins Binding to Site 5 of VGSCs 201
7 Toxins Binding to Site 6 of VGSCs 203
8 Conclusion 204
References 204
Mechanisms of Drug Binding to Voltage-Gated Sodium Channels 212
1 Introduction 213
2 Molecular Biology of Na+ Channels 214
3 Sodium Channelopathies 214
4 Structure and Function Relationships 215
5 Voltage-Dependent Gating of Na+ Channels 217
6 Mechanisms of Drug Binding and Channel Inhibition 218
7 Modulated Receptor Hypothesis 219
8 Guarded Receptor Hypothesis 221
9 Alternative Mechanisms of Drug Inhibition 222
10 Interaction Between Permeant Cations and Pore-Blocking Drugs 222
11 Drug Inhibition Is Voltage-Dependent 223
12 Modulation of Drug Binding by External Protons 224
13 Recovery from Drug Inhibition 224
14 Regulation of Drug Binding by Auxiliary ?-Subunits 226
15 Conclusion 226
References 227
Effects of Benzothiazolamines on Voltage-Gated Sodium Channels 235
1 Overview of Voltage-Gated Sodium Channels Pharmacology 236
2 Riluzole 237
2.1 Pharmacology of Riluzole 237
2.2 Molecular Effects of Riluzole on Sodium Channels 239
3 Lubeluzole 243
3.1 Pharmacology of Lubeluzole 243
3.2 Molecular Effects of Lubeluzole on Sodium Channels 244
4 Riluzole and Lubeluzole as Antimyotonic Drugs? 246
5 Conclusions 247
References 247
Structural Models of Ligand-Bound Sodium Channels 253
1 Structure of Sodium Channels 254
2 Homology Modeling and Ligand Docking 256
3 Inner Pore Blockers 257
4 Neurotoxins 263
5 Conclusion 266
References 267
Selective Ligands and Drug Discovery Targeting the Voltage-Gated Sodium Channel Nav1.7 272
1 Considerations for Selective, Therapeutic Targeting of Nav1.7 273
2 Introduction to Nav Channels 275
3 Nav Channel Structure, Biophysics, and Receptor Sites 275
4 Introduction to Nav1.7 Physiology and Channelopathies 279
5 Nav1.7 Receptor Sites: Potential for Selective Targeting 281
6 Inner Vestibule Nav Channel Antagonists 281
7 Extracellular Vestibule Selectivity Filter Blockers 283
8 Voltage-Sensor Targeting: Gating Modifying Peptides 287
8.1 The Pn3a Peptide 289
8.2 ProTx2 and Derivatives 290
9 Trapping VSD4: Identification of the Subtype Selective Aryl Sulfonamides 292
10 Opportunities and Challenges in Nav1.7 Drug Discovery 294
10.1 Pharmacokinetic Properties 295
10.2 State-Dependence of Inhibition 295
10.3 Efficiency of In Vivo Target Engagement 296
10.4 Toxicity Considerations 296
11 Perspective and Future Outlook 297
References 298
Part IV: Pathophysiology of Sodium Channels 308
Sodium Channelopathies of Skeletal Muscle 309
1 The Na+ Channel of Skeletal Muscle 310
2 Clinical Phenotypes Associated with NaV1.4 Mutations 310
3 Overview of NaV1.4 Mutations 312
3.1 Gain-of-Function Mutations Cause Myotonia and Hyperkalemic Periodic Paralysis 313
3.1.1 Gating Defects in Myotonia and HyperPP 313
3.1.2 Pathophysiologic Mechanism of Myotonia and HyperPP 315
3.2 Anomalous Gating Pore Conduction in Hypokalemic Periodic Paralysis 317
3.2.1 Gating Pore Current in HypoPP Mutant Channels 318
3.2.2 Pathophysiologic Mechanism for HypoPP 319
3.3 Loss-of-Function Mutations: Myasthenia and Congenital Myopathy 321
3.3.1 Loss-of-Function Defects in Myasthenia and Myopathy 323
3.3.2 Pathophysiologic Mechanism of Myasthenic Weakness 324
References 325
Cardiac Arrhythmias Related to Sodium Channel Dysfunction 331
1 Introduction 332
2 SCN5A Mutations and Cardiac Arrhythmias 335
2.1 Rare SCN5A Exonic Variants 335
2.1.1 Long QT Syndrome (LQTS) 335
2.1.2 J-Wave Syndromes: Brugada and Early Repolarization Syndrome 338
2.1.3 Progressive Cardiac Conduction Disease (PCCD or Lenegre-Lev Disease) 340
2.1.4 Sick Sinus Syndrome (SSS) 341
2.1.5 Sudden Infant Death Syndrome (SIDS) 341
2.1.6 Atrial Fibrillation (AF) 341
2.1.7 Dilated Cardiomyopathy Disease (DCM) 342
2.1.8 Multifocal Ectopic Purkinje-Related Premature Contractions (MEPPC) 343
2.1.9 Overlap Syndromes 343
2.2 Common SCN5A EXONIC Variants 343
2.3 Common SCN5A Intronic Variants (SCN5A-SCN10A Interaction/Regulation) 344
3 Summary 345
References 346
Translational Model Systems for Complex Sodium Channel Pathophysiology in Pain 355
1 Congenital Pain Syndromes 356
1.1 Nav1.7 in Human Pain Syndromes 356
1.2 Nav1.8 and Nav1.9 in Pain (Less) Disorders 358
2 Translation from Dish to Rodent to Human 359
2.1 Heterologous Expression of Human Proteins 360
2.2 Human DRGs as a Model System 361
2.3 Human Microneurography 362
2.4 Human Pluripotent Stem Cell-Derived Nociceptors 363
3 Concluding Remarks 366
References 366
Gating Pore Currents in Sodium Channels 370
1 Part I: Voltage Sensing Domains and Gating Pores 371
1.1 The Voltage Sensor Domain 371
1.2 Gating Pores 375
1.3 Gating Pore Currents and Action Potentials 378
2 Part II: Gating Pores and Sodium Channelopathies 378
2.1 Skeletal Muscle Channelopathies: Mutation-Based Phenotype and Gating Defects 378
2.2 Hypokalemic Periodic Paralysis: Role of the Omega Current 379
2.3 Cardiac Channelopathies 384
2.4 Cardiac Channelopathies: Role of the Omega Current 384
2.5 Pharmacology of Sodium Channelopathies Associated with Gating Pore Current 386
3 Part III: Computational Approaches to Investigate Gating Pore Current 387
3.1 Action Potential Modeling 387
3.2 All-Atom Molecular Dynamics 387
References 391
Calculating the Consequences of Left-Shifted Nav Channel Activity in Sick Excitable Cells 399
1 Introduction 400
2 Experimental Basis of the Nav-CLS Model 402
3 The Coupled Left-Shift Model (CLS) 405
4 CLS in a Node with Two Nav Populations (Intact and Damaged) and No Pumps 408
5 Excitability and CLS Damage in a Node with Pumps 410
6 CLS-Induced Pathological Activity for Realistically Complex Membrane Damage 412
7 Dynamical Analysis of Ectopic Bursting 413
8 Saltatory Propagation in Axons with Mildly Damaged Nodes 413
9 Sick Excitable Cells and Nav-CLS in Other Modeling Contexts 415
10 The CLS Model Within NEURON, the Simulation Environment 416
11 Conclusion 417
References 418
Voltage-Gated Sodium Channel ? Subunits and Their Related Diseases 421
1 The Basics of the Voltage-Gated Sodium Channel ? Subunits 422
1.1 Modulation of the Ion Channel Pore by ? Subunits 424
1.2 The ? Subunits as Cell Adhesion Molecules 428
2 The Role of ? Subunits in Pathophysiology 431
2.1 Cancer 431
2.2 Cardiac Arrhythmia 432
2.3 Epilepsy 433
2.4 Neurodegenerative Disorders 434
2.5 Neuropathic Pain 436
2.6 Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Death in Epilepsy (SUDEP) 437
3 Conclusion 438
References 439