Pharmacology of Potassium Channels (Handbook of Experimental Pharmacology, 267)

Preface
Contents
Comparison of K+ Channel Families
	1 Overview
	2 Subunits/Assembly/Topology
	3 K+ Selectivity
	4 Gating Mechanisms
	5 Role of Lipids/PIP2
	6 Trafficking and Accessory Subunits
	7 Pharmacology: Blockers and Modulators
	8 Physiology and Function
	References
High-Resolution Structures of K+ Channels
	1 Importance of High-Resolution Structures to Pharmacology of K+ Channels
	2 Phylogenetic Subfamilies of K+ Channels and Their Typical Structural Models
	3 A Simplified Gating Model for Different K+ Channels
	4 Structural Basis for Ion Selectivity of K+ Channels
	5 Structural Diversity Among Voltage-Gated Potassium (Kv) Channels and Differences in the Physical Movements of the Voltage-Se...
	6 Structural Basis Underlying the N-Type Inactivation
	7 Structure Determinants for Channels in a Steady-State Inactivation
	8 Ligand-Gated Potassium Channels and the Structural Basis for Their Gating
		8.1 Ca2+-Activated Potassium (KCa) Channels
		8.2 Structures of KATP Channels
		8.3 GPCR-Coupled K+ Channels
		8.4 Two-Pore K+ Channels (K2P)
	9 Lipid-Dependent Gating of Kv Channels, and Lipid-Soluble Pharmacological Agents
	10 Unresolved Questions on the Structural Bases of K+ Channels and Future Directions
	References
Pharmacological Approaches to Studying Potassium Channels
	1 Potassium Channel Families
		1.1 6TM Potassium Channels
		1.2 2TM Potassium Channels
		1.3 4TM Potassium Channels
	2 Classical Pharmacology of Potassium Channels
	3 Identifying K Channel Pharmacological Targets
		3.1 Physiological and Pathophysiological Role of the Channel of Interest
		3.2 Knowledge of Distribution Channel mRNA and Protein Expression in the Appropriate Places in the Body
		3.3 Are There Species Differences? This May Be Important for Extrapolation from Preclinical Physiology and/or Pharmacology Stu...
		3.4 Evidence from Diseases States of Channel Up- or Down-Regulation
		3.5 Case Study 1: TREK-2 Channel Activators for Pain
		3.6 Case Study 2: KV1.3 Channel Blockers in Autoimmune Disorders
	4 Techniques to Study the Pharmacology of K Channels
		4.1 Improved Structural Information for Ion Channels
		4.2 Flux Assays
			4.2.1 Thallium (Tl+) Flux Assay
			4.2.2 Liposome Flux Assay
		4.3 Electrophysiological Approaches
	5 Quantification and Standardisation of Drug Action on K Channels
		5.1 hERG Channels and the CiPA Initiative
	References
Cardiac K+ Channels and Channelopathies
	1 Function of Cardiac Potassium Channels
	2 Characteristics and History of Congenital Long QT Syndromes
	3 Congenital Long QT Syndromes Associated with IKs: LQT1, 5, 11
	4 IKr Associated Congenital Long QT Syndromes: LQT2 and LQT6
	5 Mutations in Kir2.1 Cause the LQT7/Andersen-Tawil Syndrome
	6 Short QT Syndrome (SQTS)
	7 Brugada Syndrome
	8 Ion Channels in Atrial Tachyarrhythmias
	9 Calmodulinopathy Leads a Path to a Potential SK Channel-Based AF Therapy
	References
Cardiac hERG K+ Channel as Safety and Pharmacological Target
	1 Introduction
	2 Structure of hERG Channel
	3 Mechanisms of Arrhythmias
	4 hERG Inhibitors
		4.1 hERG Inhibitors as Antiarrhythmic Agents
		4.2 hERG Inhibition by Structurally Diverse Drugs
		4.3 Molecular Basis Underlying hERG Channel Inhibition
		4.4 Methodology of hERG Assays
		4.5 A New CiPA Paradigm to Evaluate Drug-Induced TdP
	5 hERG Activators
		5.1 Mechanisms of Action of hERG Channel Activators
			5.1.1 Slowing the Deactivation
			5.1.2 Attenuation of C-Type Inactivation
			5.1.3 Negative Shift of Voltage Dependence of Activation
			5.1.4 Increase in Channel Open Probability
		5.2 Potential Antiarrhythmic Effect of hERG Channel Activators
		5.3 Proarrhythmic Risk of hERG Channel Activators
	6 Conclusion
	References
Pharmacology of A-Type K+ Channels
	1 Introduction
	2 Identifying Native A-Type Channels
		2.1 Biophysics
			2.1.1 Activation Range
			2.1.2 Inactivation Properties
		2.2 Pharmacology
			2.2.1 Kv3 A-Type Currents
			2.2.2 Kv1.4 A-Type Currents
			2.2.3 Kv4 A-Type Currents
	3 Physiological Roles of A Currents
		3.1 Neural Excitability and Spike Properties
		3.2 Dendritic Integration and LTP
	References
Kv7 Channels and Excitability Disorders
	1 Introduction
	2 Biophysical Properties of Kv7 Channels as a Guide to Their Role in Cellular Excitability
	3 Structural Insights into Kv7 Channel Assembly and Function
	4 Auxiliary Subunits of Kv7 Channels
		4.1 KCNEs
		4.2 A-Kinase Anchoring Proteins
		4.3 Other Kv7-Interacting Proteins
	5 Kv7 Pharmacology
	6 Tissue Distribution of Kv7 Channels
		6.1 Nervous System
		6.2 Cardiovascular System
		6.3 Non-vascular Musculature
		6.4 Epithelia
		6.5 Other Tissues and Cell Types
	7 Regulation and Modulation
	8 Transcriptional Control of Kv7 Gene Expression
	9 Kv7 Channels and Excitability Disorders
		9.1 Cardiac Arrhythmias
		9.2 Other Cardiovascular Disorders
		9.3 Deafness
		9.4 Behavioural Disorders
			9.4.1 Depression
			9.4.2 Anxiety
			9.4.3 Schizophrenia
			9.4.4 Learning, Memory and Neurodevelopmental Disorders
			9.4.5 Addiction
	10 Other Diseases and Pathologies
		10.1 Pulmonary Disorders
		10.2 Gastrointestinal Tract Disorders
		10.3 Bladder Dysfunctions
		10.4 Other Pathologies
	References
Pharmacological Activation of Neuronal Voltage-Gated Kv7/KCNQ/M-Channels for Potential Therapy of Epilepsy and Pain
	1 Introduction
	2 Distributions of Neuronal Kv7.2/7.3 Channels in the Central Nervous System (CNS) and the Peripheral Nervous System (PNS)
	3 Regulation of Kv7.2/7.3 Channels by GPCR Signaling
	4 Validation of Kv7.2/7.3 Channels as Therapeutic Targets for Epilepsy and Pain
	5 Pharmacological Activation of Neuronal Kv7 for Potential Therapy of Epilepsy and Chronic Pain
		5.1 Kv7/KCNQ/M Channel Opener Retigabine for Treatment of Partial Epilepsy
		5.2 Other KCNQ Openers for Potential Treatment of Epilepsy
		5.3 Pharmacological Activation of Kv7 by Openers for Therapy of Chronic Pain
	6 Conclusions/Perspectives
	References
Potassium Channels in Cancer
	1 Introduction
	2 Oncogenic Potassium Channels
	3 Upstream and Downstream Signalling
	4 Metabolic Reprogramming and Adaptation to Tumour Hypoxia
	5 Maintenance of Cancer Stemness
	6 Tumour Spreading and Metastasis
	7 Therapy Resistance
	8 Immune Surveillance, Immunosuppression and Anti-cancer Immune Response
	9 Repurposing Drugs for Potassium Channel-Targeting Therapies
	10 Concluding Remarks
	References
Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications
	1 Historical Perspective: The Pre-structure Era
		1.1 Tissue Distribution of Kir Family Members
		1.2 Kir Channel Gating
		1.3 Kir Channel Trafficking
		1.4 The Structural Era
			1.4.1 Kir Structures by 2020
			1.4.2 Structural Features of Kir Channels
				Selectivity Filter (SF)
				Gates
				PIP2 Binding Site
				Cholesterol Regulation
				Rectification Determinants
	2 Classical Kir2 Channels
		2.1 Historical Perspective
		2.2 Subfamily Members and Tissue Distribution
		2.3 Physiology/Pathophysiology
		2.4 Pharmacology
		2.5 Structural Studies
	3 G Protein Kir3 Channels
		3.1 Historical Perspective
		3.2 Subfamily Members and Tissue Distribution
		3.3 Physiology/Pathophysiology
		3.4 Pharmacology
			3.4.1 Inhibitors in Disease
			3.4.2 Activators in Disease
		3.5 Structural Studies
	4 ATP-Sensitive Kir6 Channels
		4.1 Introduction
		4.2 Channel Regulation and Trafficking
		4.3 Physiology/Pathophysiology and Tissue Distribution
		4.4 Pharmacology
			4.4.1 Drugs Acting Through the Kir6 Subunits
		4.5 Structural Studies
	5 K+ Transport Kir (1, 4, 4/5, 7) Channels
		5.1 Kir1.1: Historical Perspective
			5.1.1 Subfamily Members and Tissue Distribution
			5.1.2 Physiology/Pathophysiology
		5.2 Kir4/Kir5: Historical Perspective and Tissue Distribution
			5.2.1 Physiology/Pathophysiology
		5.3 Kir7.1: Historical Perspective
			5.3.1 Tissue Distribution
			5.3.2 Physiology/Pathophysiology
		5.4 Transport Channel Pharmacology
			5.4.1 Transport Channel Structural Determinants
				Kir1, 4, and 7 Channel Structure and Dynamics
	6 Conclusions
	Appendix
	References
The Pharmacology of ATP-Sensitive K+ Channels (KATP)
	1 Introduction
	2 The Structure and Regulation of KATP Channels
	3 The Pharmacological Properties of KATP Channels
		3.1 KATP Channel Openers
		3.2 KATP Channel Blockers
			3.2.1 Sulfonylureas
			3.2.2 Nonsulphonylurea Drugs
			3.2.3 KATP Channel Pore Blockers
	4 The Physiology and Pathophysiology of KATP Channels
		4.1 Pancreas
		4.2 Heart
		4.3 Cantu Syndrome
		4.4 Sudden Infant Death Syndrome
		4.5 Nervous System
		4.6 Pulmonary Circulation
		4.7 Current Therapeutic Uses of KCOs and Inhibitors of KATP Channel
	5 Conclusions
	References
Calcium-Activated K+ Channels (KCa) and Therapeutic Implications
	1 K+ Channels
		1.1 Ca2+ Activated K+ Channels
		1.2 BK Channel Physiology
		1.3 BK Channel Pathophysiology
	2 BK Channel Auxiliary Subunits
		2.1 BK Channel β Subunits
		2.2 β1 Subunit
		2.3 β1 Subunit Specific Effects on BK Channel Activation
		2.4 β2 Subunit
		2.5 β3 Subunit
		2.6 β4 Subunit
		2.7 BK Channel γ Subunits
	3 BK Channel Structure
		3.1 Voltage Sensor Domain (VSD)
		3.2 Voltage Dependent Activation
		3.3 Cytosolic Tail Domain (CTD)
		3.4 Calcium Dependent Activation
		3.5 Pore Gate Domain (PGD)
		3.6 Activation Gate
		3.7 Allosteric Gating of BK Channels
		3.8 Calcium Sensor/Gate Coupling
		3.9 Voltage Sensor/Gate Coupling
	4 BK Channel Activators
		4.1 Endogenous BK Channel Activators
		4.2 Natural BK Channel Activators
		4.3 Synthetic BK Channel Activators
		4.4 Lack of Selectivity of BK Channel Openers
	5 SK Channel Modulators
	6 IK Channel Modulators
	References
The Pharmacology of Two-Pore Domain Potassium Channels
	1 An Introduction to Two-Pore Domain Potassium Channels
	2 The Role of K2P Channels in Pathology and Pain Signaling
		2.1 K2P Channel Pharmacology
	3 The THIK Channels: K2P12 and K2P13
	4 The TRESK Subfamily: K2P18
	5 The TALK Subfamily: K2P5, K2P16, and K2P17
	6 The TWIK Subfamily: K2P1, K2P6, and K2P7
	7 The TREK Subfamily: K2P2, K2P10, and K2P4
	8 The TASK Subfamily: K2P3, K2P9, and K2P15
	9 TOK Channels
	10 Conclusion and Future Perspectives
	References
Control of Biophysical and Pharmacological Properties of Potassium Channels by Ancillary Subunits
	1 Introduction
	2 Ancillary Subunit Modulation of K+ Channel Function
		2.1 Obligate Ancillary Subunit Interactions, Essential for Channel Activity
		2.2 Ancillary Subunit Interactions Not Necessary for Channel Function But Essential for a Known Physiological Role
			2.2.1 KCNE1 Effects on KCNQ1 Function
			2.2.2 KCNE1 Effects on KCNQ1 Trafficking
			2.2.3 Effects of KCNE2 on KCNQ1 Function and Trafficking
			2.2.4 Effects of KCNE3 on KCNQ1 Function
			2.2.5 SK Regulatory Proteins and BK γ Subunits
			2.2.6 BK β Subunits
			2.2.7 Cytosolic Subunits that Add Novel Functionality to Kv Channels
			2.2.8 SUMO and 14-3-3 Interactions with K2P Channels
		2.3 Ancillary Subunit Interactions Inhibitory to Channel Activity
	3 Ancillary Subunit Modulation of K+ Channel Pharmacology
		3.1 Sensitization by Providing a Novel Binding Site Absent from the Channel α Subunit to Directly Impact Channel Function
		3.2 Sensitization by Increasing the Affinity of a Small Molecule That Also Binds to and Modulates α Subunit-Only Channels
			3.2.1 Modulation of KCNQ1 Pharmacology by KCNEs
			3.2.2 Wild-Type and Inherited Mutant KCNE2 Effects on hERG Pharmacology
			3.2.3 G Protein βγ (Gβγ) Subunits
		3.3 Desensitization by Decreasing the Affinity of a Small Molecule That Binds to and Modulates α Subunit-Only K+ Channels
	4 Conclusions
	References
Peptide Toxins Targeting KV Channels
	1 Introduction
	2 Classification of Peptide Toxins Targeting K+ Channels
	3 Pore-Blocking Toxin
		3.1 Overview
		3.2 K+ Channel Inhibition by CTX in the Pore-Plugging Mechanism
		3.3 Pore-Blocking Toxin with a Distinct Structural Fold
		3.4 Peptide Toxins That Bind to the PD with Indirect Inhibition Mechanisms
	4 Gating-Modifier Toxins
		4.1 Overview
		4.2 The S3-S4 Region of VSD Is the Binding Site of Gating-Modifier Toxins
		4.3 Hydrophobic Surface Contributing to the Inhibition of Gating-Modifier Toxins
		4.4 Voltage-Dependent Inhibition of KV Channel by Gating-Modifier Toxins
		4.5 Gating-Modifier Toxins Binding to the Depolarised Conformation of VSD
	5 Conclusion
	References
Therapeutic Antibodies Targeting Potassium Ion Channels
	1 K+ Channels as Targets for Therapeutic Antibody Development
		Box 1 Antibody Discovery
	2 Antibody Discovery and Development: Challenges and Opportunities
		2.1 Theoretical Considerations
		2.2 Practical Considerations
	3 Workflows in Antibody Production and Screening
		3.1 Choice of Immunogen
		3.2 Expression Platforms for Antigen Generation
		3.3 Purification and Formulation of Target Immunogens
		3.4 Antibody Platforms and Initial Phases of Screening
		3.5 Functional Screening Assays
	4 Current Status of the Field
		4.1 Kv1.3
		4.2 Kv10.1
		4.3 Kv11.1 (hERG)
		4.4 TASK3
	5 Concluding Remarks
	References