Textbook of Ion Channels Volume II: Properties, Function, and Pharmacology of the Superfamilies

Cover
Half Title
Title Page
Copyright Page
Table of Contents
Preface
Editors
Contributors
Chapter 1 Taxonomy and Evolution of Ion Channels
	1.1 How Should We Approach Ion Channel Taxonomy?
	1.2 Ion Channel Superfamilies Have Independent Evolutionary Origins
	1.3 Structural Diversification of the Voltage-Gated Cation Channel (VGIC) Superfamily
	1.4 Ion Channel Families and Subfamilies
	1.5 Evolutionary History of Ion Channels: Ancient Structures and Dynamic Gene Sets
	1.6 Much of the Genetic Diversity of Ion Channels Remains Unexplored
	Suggested Reading
Chapter 2 Voltage-Gated Sodium Channels
	2.1 Functional Roles of Voltage-Gated Sodium Channels
		2.1.1 Action Potential Generation and Propagation
		2.1.2 Activation, Conductance and Two Phases of Inactivation
		2.1.3 Persistent and Resurgent Sodium Currents
	2.2 Discovery and Biochemical Properties of the Sodium Channel Protein
		2.2.1 Identification, Purification and Reconstitution of Sodium Channels
		2.2.2 Primary Structures of Sodium Channel Subunits
		2.2.3 Mapping the Molecular Components Required for Sodium Channel Function
	2.3 Three-Dimensional Structure of the Sodium Channel
		2.3.1 Structure of Bacterial Sodium Channels
		2.3.2 The Pore Contains a High-Field-Strength Carboxyl Site and Two Carbonyl Sites
		2.3.3 Voltage-Sensor Structure
		2.3.4 Voltage-Dependent Activation Involves a Sliding-Helix Mechanism
		2.3.5 An Iris-Like Movement Opens the Pore
	2.4 The Pore Collapses during Slow Inactivation
	2.5 Drugs Block the Pores of Sodium Channels
	2.6 Evolutionary Additions to Mammalian Sodium Channels
	2.7 Sodium Channel Diversity
	Suggested Reading
Chapter 3 Voltage-Gated Calcium Channels
	3.1 Introduction
	3.2 VGCC Diversity, Nomenclature and Structural Organization
	3.3 Physiological Roles of VGCCs
	3.4 Gating of VGCCs
	3.5 Ion Permeability of VGCCs
	3.6 Pharmacology of VGCCs
	3.7 Regulation of VGCCs
	3.8 Biogenesis, Trafficking and Turnover of VGCCs
	3.9 VGCC Channelopathies and Disease
	3.10 Conclusion
	Suggested Reading
Chapter 4 Voltage-Gated Potassium Channels
	4.1 Introduction
	4.2 Structure of Kv Channels
	4.3 The Pore Domain
	4.4 Ionic Selectivity and Permeation
	4.5 Voltage-Sensor Domains and the Mechanism of Voltage Gating
	4.6 N-Type and C-Type Inactivation
	4.7 Kv Channel Families
		4.7.1 The Kv1 Family
		4.7.2 The Kv2 Family
		4.7.3 The Kv3 Family
		4.7.4 The Kv4 Family
		4.7.5 Kv5, Kv6, Kv8 and Kv
	4.8 Pharmacology of Kv Channels
	4.9 Kv Channel Accessory Proteins
	4.10 Biogenesis of Kv Channels
	4.11 Unresolved Questions and Research Directions
	Acknowledgments
	Suggested Reading
Chapter 5 ERG Family of Potassium Channels
	5.1 Introduction
	5.2 Physiological Roles
	5.3 Subunit Diversity and Basic Structural Organization
	5.4 Channel Physiology and Gating Mechanisms
		5.4.1 Physiology
			5.4.1.1 ERG
			5.4.1.2 EAG
			5.4.1.3 ELK
		5.4.2 Gating Mechanisms
			5.4.2.1 ERG
			5.4.2.2 EAG
			5.4.2.3 ELK
	5.5 Ion Permeability
	5.6 Regulation
	5.7 Cell Biology (Biogenesis, Trafficking, Turnover)
	5.8 Channelopathies and Disease
	5.9 Pharmacology
		5.9.1 hERG, IKr and Acquired LQTS
	5.10 Conclusion
	Suggested Reading
Chapter 6 KCNQ Channels
	6.1 Introduction
	6.2 Physiological Roles
	6.3 Channel Diversity/Structural Organization
	6.4 Gating
	6.5 Ion Permeability
	6.6 Pharmacology
	6.7 Regulation
	6.8 Cell Biology (Biogenesis and Trafficking)
	6.9 Channelopathies
	6.10 Conclusions
	Suggested Reading
Chapter 7 BK channels
	7.1 Functional Properties of BK Channels
	7.2 Physiological Roles of BK Channels
	7.3 BK Channel Structure
	7.4 Allosteric Mechanisms of BK Channel Activation
	7.5 Structural Basis of BK Channel Function
		7.5.1 Large Single-Channel Conductance
		7.5.2 Voltage- and Ca2+-Dependent Activation
		7.5.3 Activation by Other Intracellular Ions
	7.6 β and γ Subunits Modulate BK Channel Function
	7.7 Pharmacology of BK Channels
	7.8 Concluding Remarks
	Acknowledgments
	Suggested Reading
Chapter 8 Small-Conductance Calcium-Activated Potassium (SK) Channels
	8.1 Introduction
	8.2 Physiological Function
	8.3 Subunit Diversity and Structure
	8.4 Gating and Ion Permeability
	8.5 Pharmacology
	8.6 Regulation
	8.7 Cell Biology (Biogenesis, Trafficking, Turnover)
	8.8 Channelopathies and Disease
	8.9 Conclusions
	Suggested Reading
Chapter 9 Inward Rectifier Potassium Channels
	9.1 Introduction
	9.2 Physiological Roles
	9.3 Subunit Diversity and Basic Structural Organization
	9.4 Gating of Kir Channels
		9.4.1 Regulators of Kir Channel Gating
		9.4.2 Conformational Changes during Kir Channel Gating
	9.5 Ion Selectivity and Conduction
	9.6 Pharmacology
		9.6.1 Peptide Toxins
	9.7 Regulation
	9.8 Cell Biology: Biogenesis, Trafficking, Subcellular Targeting
	9.9 Kir Channelopathies
	9.10 Conclusion
	Acknowledgments
	Suggested Reading
Chapter 10 Two-Pore-Domain Potassium Channels
	10.1 Introduction to the Physiology of K2P Channels
	10.2 Structural Organization and Subunit Diversity
	10.3 Gating K2P Channels
	10.4 The Regulation and Cell Biology of the K2P Channels
		10.4.1 K2P1, K2P6 and K2P7 Channels
		10.4.2 K2P2, K2P4 and K2P10 Channels: Polymodal Rheostats
		10.4.3 The Acid-Sensitive Channels: K2P3 and K2P
		10.4.4 Alkaline-Activated Channels: K2P5, K2P16 and K2P17
		10.4.5 K2P12 and K2P13 Channels
		10.4.6 K2P18 Channels and the Pathophysiology of Pain
	10.5 Pharmacology and Emerging Perspectives on the Role of K2P Channels in Pathophysiology
	10.6 Conclusions
	Suggested Reading
Chapter 11 Cyclic Nucleotide-Gated Channels
	11.1 Introduction
	11.2 Physiological Roles of CNG Channels
	11.3 CNG Channel Subunit Diversity and Structural Organization
	11.4 Gating of CNG Channels
		11.4.1 Ligand Binding at CNBD
		11.4.2 Gating Conformational Changes through C-Linker Module to Pore Gate of CNG Channels
		11.4.3 CNG Channel Activation Schemes and Subunit Contributions
	11.5 Pore Properties of CNG Channels
	11.6 Pharmacology of CNG Channels
	11.7 Regulation of CNG Channels
	11.8 CNG Channel Cell Biology
	11.9 CNG Channel Disease Mechanisms
	11.10 Conclusions
	Suggested Reading
Chapter 12 HCN Channels
	12.1 Introduction
	12.2 Basic Structural Organization and Subunit Diversity
	12.3 Gating
	12.4 Ion Permeability
	12.5 Regulation and Cell Biology
	12.6 Pharmacology
	12.7 Physiological Roles
		12.7.1 Cardiac Pacemaking
		12.7.2 HCN Channel Function in the Nervous System
	12.8 Channelopathies, Disease, and Therapeutic Opportunities
	12.9 Conclusions
	Suggested Reading
Chapter 13 CLC Chloride Channels and Transporters
	13.1 Introduction
	13.2 Physiological Roles
		13.2.1 CLC Channels
		13.2.2 CLC Transporters
	13.3 Subunit Diversity and Basic Structural Organization
	13.4 Gating
		13.4.1 CLC Channels
		13.4.2 CLC Transporters
	13.5 Ion Permeability
	13.6 Pharmacology
	13.7 Regulation
	13.8 Cell Biology
	13.9 Channelopathies and Disease
	13.10 Conclusions
	Acknowledgments
	Suggested Reading
Chapter 14 Calcium-Activated Cl– Channels
	14.1 Introduction
	14.2 Physiological Roles
	14.3 Tmem16/Anoctamin Channels
		14.3.1 Physiological Roles
		14.3.2 Subunit Diversity and Basic Structural Organization
		14.3.3 Gating
		14.3.4 Ion Permeability
		14.3.5 Pharmacology
		14.3.6 Regulation
		14.3.7 Cell Biology (Biogenesis, Trafficking, Turnover)
	14.4 Bestrophins
		14.4.1 Physiological Roles
		14.4.2 Subunit Diversity and Basic Structural Organization
		14.4.3 Gating
		14.4.4 Ion Permeability
		14.4.5 Pharmacology
		14.4.6 Regulation
		14.4.7 Cell Biology
	14.5 Channelopathies and Disease
		14.5.1 TMEM16A and Cancer
		14.5.2 TMEM16A Genetic Diseases
		14.5.3 BEST1-Linked Diseases
	14.6 Conclusions
	Suggested Reading
Chapter 15 Acetylcholine Receptors
	15.1 Introduction
	15.2 Subunit Diversity and Cell Distribution
	15.3 Physiological Roles
	15.4 Structural Organization
		15.4.1 Extracellular Domain (ECD) and Neurotransmitter Binding Sites
		15.4.2 Transmembrane Domain (TMD) and Ion Permeation Pathway
		15.4.3 Intracellular Domain (ICD)
		15.4.4 Structural Changes for Activation
	15.5 Molecular Function and Channel Gating
	15.6 Pharmacology and Drug Modulation
		15.6.1 Orthosteric Ligands
		15.6.2 Allosteric Ligands
	15.7 Channelopathies and Disease
		15.7.1 Muscle and Ganglionic Diseases
		15.7.2 Neurological and Neurodegenerative Disorders
		15.7.3 Nicotine Dependence
		15.7.4 Cancer and Inflammatory Disorders
	15.8 Cell Biology and Regulation
	15.9 Conclusions
	Suggested Reading
Chapter 16 Ionotropic Glutamate Receptors
	16.1 Introduction
	16.2 Subunit Diversity; Genes/Paralogs/Orthologs/Subtypes; Alternative Splicing; Evolutionary Relationships
		16.2.1 Splice Variation and RNA Editing
	16.3 Structure/Organization
	16.4 Physiological Roles; Expression Pattern
		16.4.1 Basal Synaptic Transmission
		16.4.2 Control of Vesicle Release
		16.4.3 Synaptogenesis
		16.4.4 Synaptic Plasticity: LTP and LTD
		16.4.5 Short-Term Plasticity
		16.4.6 Homeostasis
		16.4.7 Expression Outside the Brain
	16.5 Pore Properties (Selectivity, Permeation, Gate)
	16.6 Pharmacology/Blockers
		16.6.1 Competitive Antagonists
		16.6.2 Noncompetitive Antagonists and Allosteric Modulators
		16.6.3 Pore Blockers
		16.6.4 Optical Methods
	16.7 Gating Mechanisms, Agonist Selectivity, Subunit Contributions and Interactions
		16.7.1 LBD Closure as the Driving Force of Channel Activation
		16.7.2 Kinetics of Activation
		16.7.3 Channel Gating
		16.7.4 Intersubunit Interactions
		16.7.5 Subunit Gating
	16.8 Regulation (Second Messengers, Mechanisms, Related Physiology)
		16.8.1 Phosphorylation
		16.8.2 Other Posttranslational Modifications
		16.8.3 Glutamate Receptor Action without Ion Flux
	16.9 Cell Biology (Assembly, Trafficking, Associated Proteins)
		16.9.1 Assembly
		16.9.2 Transmembrane AMPA Receptor-Associated Proteins (TARPs)
		16.9.3 Neto
		16.9.4 Synaptic Trapping and Auxiliary Proteins
	16.10 Channelopathies and Disease Mechanisms
	Suggested Reading
Chapter 17 5-HT3 Receptors
	17.1 Introduction
	17.2 Subunit Diversity
	17.3 Structure
		17.3.1 The Extracellular Domain
		17.3.2 The Transmembrane Domain
		17.3.3 The Intracellular Domain
	17.4 Physiological Roles and Expression
	17.5 Biophysical Properties
		17.5.1 Receptor Activation
		17.5.2 Ions and Ionic Selectivity
		17.5.3 Single-Channel Conductance
		17.5.4 The Channel Gate
	17.6 Pharmacology
		17.6.1 5-HT3 Receptor Agonists
		17.6.2 5-HT3 Receptor Antagonists
		17.6.3 5-HT3 Receptor Modulators
	17.7 Regulation
	17.8 Cell Biology
	17.9 Channelopathies and Therapeutic Potential
	Suggested Reading
Chapter 18 GABAA Receptors
	18.1 Introduction
	18.2 Receptor Subunit Diversity and Structure
	18.3 Receptor Trafficking and Clustering
	18.4 Receptor Activation and GABA Binding Sites
	18.5 Ion Channel Domain: Conductance and Ion Selection
	18.6 Biophysical Properties of GABAARs: Influence of Subunit Composition
	18.7 Modulation of GABAARs
		18.7.1 ECD Interfacial Binding Sites: Agonists
		18.7.2 Interfacial Binding Sites: Antagonists
		18.7.3 Interfacial Binding Sites: Positive Allosteric Modulators
		18.7.4 Interfacial Binding Sites: The Non-GABA Binding Interface
		18.7.5 Transmembrane Domain Binding Sites: Intrasubunit and Interfacial
		18.7.6 Transmembrane Binding Sites: The Ion Channel Pore
	18.8 Conclusions
	Suggested Reading
Chapter 19 Glycine Receptors
	19.1 Introduction
	19.2 Subunit Diversity and Basic Structural Organization
		19.2.1 Structural Organization
	19.3 Physiological Roles
	19.4 Gating
	19.5 Ion Permeability and Conductance
	19.6 Pharmacology
	19.7 Trafficking, Clustering and Regulation
	19.8 Channelopathies and Disease
	19.9 Conclusions
	Suggested Reading
Chapter 20 Acid-Sensing Ion Channels
	20.1 Introduction
	20.2 Tissue Distribution
	20.3 Function
	20.4 Agonists, Modulators and Inhibitors
		20.4.1 Agonists and Modulators
		20.4.2 Inhibitors
	20.5 Biophysical Properties
		20.5.1 Structure and Gating
		20.5.2 Desensitization
		20.5.3 Ion Selectivity
	20.6 Perspectives
	Suggested Reading
Chapter 21 ENaC Channels
	21.1 Introduction
	21.2 Physiological Roles
		21.2.1 ENaC in Epithelial Cells
		21.2.2 ENaC in Non-Epithelial Tissues and Cells
	21.3 Subunit Diversity and Basic Structural Organization
	21.4 Gating
	21.5 Ion Permeability
	21.6 Pharmacology of ENaC
	21.7 Regulation of ENaC
	21.8 Cell Biology of ENaC: Biogenesis, Trafficking and Turnover
	21.9 Channelopathies and Disease
	21.10 Conclusion
	Suggested Reading
Chapter 22 TRPC Channels
	22.1 Introduction
	22.2 Physiological Roles
	22.3 Subunit Diversity and Basic Structural Organization
	22.4 Gating
	22.5 Ion Permeability
	22.6 Pharmacology
	22.7 Regulation
	22.8 Channelopathies and Disease
	22.9 Conclusions
	Suggested Reading
Chapter 23 TRPM Channels
	23.1 Introduction
	23.2 TRPM
		23.2.1 Molecular Structure
		23.2.2 Cellular Function
	23.3 TRPM
		23.3.1 Molecular Structure
		23.3.2 Cellular Function
	23.4 TRPM
		23.4.1 Molecular Structure
		23.4.2 Cellular Function
	23.5 TRPM
		23.5.1 Molecular Structure
		23.5.2 Cellular Function
	23.6 TRPM
		23.6.1 Molecular Structure
		23.6.2 Cellular Functions
	23.7 TRPM
		23.7.1 Molecular Structure
		23.7.2 Cellular Functions
	23.8 TRPM
		23.8.1 Molecular Structure
		23.8.2 Cellular Function
	23.9 TRPM
		23.9.1 Molecular Structure
		23.9.2 Cellular Function
	Acknowledgments
	Suggested Reading
Chapter 24 TRPV Channels
	24.1 Introduction
	24.2 Physiological Roles
		24.2.1 TRPV
		24.2.2 TRPV
		24.2.3 TRPV
		24.2.4 TRPV
		24.2.5 TRPV5 and TRPV
	24.3 Subunit Diversity and Basic Structural Organization
	24.4 Gating by Temperature and Ligands
	24.5 Ion Permeability and Pharmacology
	24.6 Regulation
	24.7 Biogenesis, Trafficking and Turnover
	24.8 Channelopathies
	24.9 Conclusions
	Acknowledgments
	Suggested Reading
Chapter 25 Store-Operated CRAC Channels
	25.1 Introduction
	25.2 Biophysical Properties of CRAC Channels
	25.3 STIM1 Is the ER Ca2+ Sensor for CRAC Channel Activation
	25.4 ORAI1 Is the Prototypic CRAC Channel Protein
	25.5 Activation of STIM1: Oligomerization and Redistribution to ER–Plasma Membrane Junctions
	25.6 STIM1 Binds Directly to ORAI
	25.7 Pore Architecture and Gating
	25.8 Tissue Distribution of STIM and ORAI Proteins
	25.9 Physiological Functions of CRAC Channels
		25.9.1 T Cells
		25.9.2 Platelets
		25.9.3 Skeletal Muscle
		25.9.4 Nervous System
		25.9.5 Cell Proliferation and Cancer
	25.10 Conclusions
	Acknowledgments
	Suggested Reading
Chapter 26 Piezo Channels
	26.1 Introduction
	26.2 Physiological Roles
	26.3 Subunit Diversity and Basic Structural Organization
	26.4 Gating
	26.5 Ion Permeability
	26.6 Pharmacology
	26.7 Regulation
	26.8 Cell Biology
	26.9 Channelopathies and Disease
	26.10 Conclusions
	Suggested Reading
Chapter 27 Ryanodine Receptors
	27.1 Introduction
	27.2 Physiological Role
	27.3 Subunit Diversity and Basic Structural Organization
	27.4 Gating and Ion Permeability
	27.5 Pharmacology
	27.6 Regulation
	27.7 Cell Biology (Biogenesis, Trafficking, Turnover)
	27.8 Channelopathies and Disease
	27.9 Conclusions
	Suggested Reading
Chapter 28 Proton Channels
	28.1 Introduction
	28.2 OTOP Channel Introduction
		28.2.1 Physiological Roles of OTOP1 in Vestibular and Taste Systems
		28.2.2 Gene Structure, Subunit Diversity, and Structure of OTOP Channels
		28.2.3 Ion Selectivity, Pharmacology, and Gating of OTOP Channels
		28.2.4 OTOP Channels Distribution and Related Diseases
	28.3 Hv1 Channel Introduction
		28.3.1 Physiological Roles of Hv1 Channels
		28.3.2 Hv1 Structure
		28.3.3 Hv1 Channel Gating
		28.3.4 Ion Permeation and Selectivity in Hv
		28.3.5 Hv1 Pharmacology
		28.3.6 Hv1 Regulation
	Note
	Suggested Reading
Chapter 29 P2X Receptors
	29.1 Introduction
	29.2 Physiological Roles
	29.3 Subunit Diversity and Basic Structural Organization
	29.4 Gating
	29.5 Ion Permeability
	29.6 Pharmacology
	29.7 Regulation
	29.8 Cell Biology (Biogenesis, Trafficking, Turnover)
	29.9 Channelopathies and Disease
	29.10 Conclusion
	Suggested Reading
Index