Ion Channels in Biophysics and Physiology

Contents
Part I: Biophysical Mechanism
	Chapter 1: Venom-Derived Peptides Inhibiting Voltage-Gated Sodium and Calcium Channels in Mammalian Sensory Neurons
		1.1 Introduction
			1.1.1 Sensory Neurons and Pain Signaling
			1.1.2 Venom-Derived Peptides
		1.2 Voltage-Gated Sodium Channels
		1.3 Voltage-Gated Calcium Channels
		References
	Chapter 2: Advancing Ion Channel Research with Automated Patch Clamp (APC) Electrophysiology Platforms
		2.1 Introduction
		2.2 APC Platforms: Key Developments Over Two Decades
		2.3 Early APC Adoption: Ion Channels in Drug Discovery
		2.4 APC: Advancing Ion Channel Research
			2.4.1 Control of Internal Cell Solution Dialysis or Exchange
			2.4.2 Control of Experimental Temperature
			2.4.3 Recording Site Fluid Applications: Microfluidics and Fixed-Well
			2.4.4 Planar Patch Clamp Recording Plates
			2.4.5 Multi-Hole Patch Clamp
			2.4.6 Pressure Control
			2.4.7 Optogenetics and Optical Stimulation
		2.5 Concluding Remarks
		References
	Chapter 3: Ion Channels in Biophysics and Physiology: Methods and Challenges to Study Mechanosensitive Ion Channels
		3.1 Mechanical Properties of Biological Materials
		3.2 Detection of Mechanical Forces at the Cellular Level
		3.3 Principles of Mechano-Electrical Transduction in Mechanosensitive Ion Channels
		3.4 Families of Mechanosensitive Ion Channels
		3.5 Experimental Methods to Stimulate Mechanosensitive Ion Channels
		3.6 Computational Approaches to Study Gating Mechanisms in Mechanosensitive Ion Channels
		References
	Chapter 4: The Polysite Pharmacology of TREK K2P Channels
		4.1 Introduction
		4.2 The TREK Subfamily: Model Polymodal Ion Channels
		4.3 The Polysite Pharmacology of TREK Channels
			4.3.1 The Keystone Inhibitor Site: Block by Polynuclear Ruthenium Amines
			4.3.2 The K2P Modulator Pocket: A Cryptic Small Molecule Binding Site for K2P Control
			4.3.3 The Fenestration Site: A Binding Site for Activators and Inhibitors
			4.3.4 The Modulatory Lipid Site: PIP2 and the C-Terminal Tail
		4.4 Subtype Specific Modulators in the TREK Subfamily
		4.5 Perspectives on K2P Channel Polysite Pharmacology
		References
	Chapter 5: Calcium Channel Splice Variants and Their Effects in Brain and Cardiovascular Function
		5.1 Ion Channels in Biophysics and Physiology
			5.1.1 Introduction to LTCC
			5.1.2 Structure and Localization of LTCC
			5.1.3 LTCC in the Cardiovascular System-Function
			5.1.4 Channelopathies in the CVS-Cav1.2
				5.1.4.1 Timothy Syndrome
				5.1.4.2 Brugada Syndrome
			5.1.5 Channelopathies in the CVS-Cav1.3
				5.1.5.1 Cardiac Dysfunction/Arrhythmia
			5.1.6 Regulation of Cav1.2
			5.1.7 Conclusion
		5.2 CaV2.1
			5.2.1 History of CaV2.1 Channel
			5.2.2 CaV2.1 Channel Diversity
			5.2.3 Exon 31
			5.2.4 Exon 37
			5.2.5 Exon 43/44
			5.2.6 Exon 47
			5.2.7 Modulation of Calcium Channels
				5.2.7.1 Voltage-Dependent Inactivation (VDI)
				5.2.7.2 Ca2+-Dependent Inactivation (CDI)
				5.2.7.3 Ca2+-Dependent Facilitation (CDF)
				5.2.7.4 CaV2.1 Channelopathies
			5.2.8 Episodic Ataxia Type 2 (EA2)
			5.2.9 Familial Hemiplegic Migraine Type 1 (FHM1)
			5.2.10 Spinocerebellar Ataxia Type 6 (SCA6)
			5.2.11 Psychiatric Disorders
		5.3 Conclusion
		References
	Chapter 6: Structure-Function of TMEM16 Ion Channels and Lipid Scramblases
		6.1 Introduction
		6.2 Molecular Identifications of TMEM16 Proteins
			6.2.1 TMEM16A and TMEM16B Form the Canonical Ca2+-Activated Chloride Channels
			6.2.2 TMEM16F Encodes a Dual Functional CaPLSase and Nonselective Ion Channel
		6.3 Structure and Function of TMEM16 Proteins
			6.3.1 Biophysical Properties of TMEM16 Ion Channels
			6.3.2 Fluorescence Methods Enable Biophysical Characterization of TMEM16 CaPLSases
			6.3.3 Overall Architecture of TMEM16 Proteins
			6.3.4 Ca2+-Dependent Activation Mechanism
			6.3.5 Voltage-Dependent Activation of TMEM16 Ion Channels
			6.3.6 Ion Selectivity of the TMEM16A/B CaCCs
			6.3.7 Ion Selectivity of the Dual-Functional TMEM16F
			6.3.8 Phospholipid Permeation Through TMEM16 CaPLSases
				6.3.8.1 Classical ``Credit Card´´ Model for Phospholipid Permeation
				6.3.8.2 Membrane Bending/Distortion Is a Common Feature in TMEM16 Scramblases
				6.3.8.3 ``Lipidic Pore´´ Dual Permeation Model Derived from the ``Credit-Card´´ Model
				6.3.8.4 ``Ions-in-the-Pore and Lipids-Out-of-the-Groove´´ Dual Permeation Model
				6.3.8.5 ``Alternating Pore-Cavity´´ Dual Permeation Model
			6.3.9 TMEM16 CaPLSase Gating
		6.4 Future Prospective
		References
	Chapter 7: Distribution and Assembly of TRP Ion Channels
		7.1 Introduction
		7.2 Distribution of TRP Channels and Its Implications for Health
			7.2.1 Cellular Distribution of TRP Channels
			7.2.2 TRP Channels Distribution in Healthy Tissues and Organs
				7.2.2.1 Distribution of TRPCs in Mammals
					TRPC1
					TRPC2
					TRPC3
					TRPC4
					TRPC5
					TRPC6
					TRPC7
				7.2.2.2 Distribution of TRPMs in Mammals
					TRPM1
					TRPM2
					TRPM3
					TRPM4
					TRPM5
					TRPM6
					TRPM7
					TRPM8
				7.2.2.3 Distribution of TRPVs in Mammals
					TRPV1
					TRPV2
					TRPV3
					TRPV4
					TRPV5
					TRPV6
				7.2.2.4 Distribution of TRPA1 in Mammals
				7.2.2.5 Distribution of TRPMLs in Mammals
				7.2.2.6 Distribution of TRPPs in Mammals
			7.2.3 TRP Channels in Abnormal Tissues and Organs
				7.2.3.1 TRP Channels Distribution in Cancers
				7.2.3.2 TRP Channels in Other Diseases
		7.3 Assembly of TRP Channels
			7.3.1 Intra-Subunit Interactions Affecting TRP Channel Assembly and Trafficking
			7.3.2 Assembly of TRP Channels Within and Between Subfamilies
				7.3.2.1 Assembly Within TRP Subfamilies
				7.3.2.2 Assembly Between TRP Subfamilies
			7.3.3 Assembly Between TRPP Channels and Receptor-like Polycystin-1 Family Proteins
			7.3.4 Specificity of TRP Channel Subunits Co-Assembly
		7.4 Discussion and Outlook
			7.4.1 Relevance of TRP Channel Distribution to Their Function
			7.4.2 Deciphering TRP Channel Assembly for a Better Understanding of Their Distribution and Functions
			7.4.3 Summary
		References
	Chapter 8: Regulation of Ion Channel Function by Gas Molecules
		8.1 Ion Channels in General
		8.2 Chemical Physics of Gasotransmitters in General
		8.3 Ion Channel Modification Via NO-Mediated S-Nitrosylation
			8.3.1 NMDA Receptors
			8.3.2 Voltage-Gated Na+ Channels
			8.3.3 Acid Sensing Ion Channels (ASICs)
			8.3.4 Cyclic-Nucleotide-Gated Ion Channels
			8.3.5 Transient Receptor Potential Channels
			8.3.6 Voltage-Gated K+ Channels
			8.3.7 ATP-Sensitive Potassium Channels
			8.3.8 Large-Conductance Ca2+-Activated K+ Channels
			8.3.9 Voltage-Gated Ca2+ Channels
			8.3.10 Ryanodine Receptors
		8.4 Ion Channel Modification Via H2S and S-Sulfhydration
			8.4.1 ATP-Sensitive Potassium Channels
			8.4.2 Transient Receptor Potential Channels
			8.4.3 L-Type Calcium Channels
		8.5 Singlet Oxygen
		8.6 Carbon Monoxide (CO) as a Gasotransmitter and Crosstalk Among Different Regulatory Pathways
		References
	Chapter 9: DEG/ENaC Ion Channels in the Function of the Nervous System: From Worm to Man
		9.1 Introduction
		9.2 DEG/ENaC Channels Structure
		9.3 Modulation of DEG/ENaCs by Homologous and Accessory Subunits
		9.4 Neuronal DEG/ENaC Channels in Mechanosensation
		9.5 Neuronal DEG/ENaC Channels in Other Sensory Modalities
		9.6 DEG/ENaC Channels in Neurotoxicity and Axonal Degeneration
		9.7 C. elegans DEG/ENaC Channel UNC-8 is Involved in Synaptic Remodeling
		9.8 DEG/ENaC Channels in Synaptic Transmission
		9.9 Expression and Function of DEG/ENaC Channels in Glia
		References
Part II: Physiological Function
	Chapter 10: Glial Chloride Channels in the Function of the Nervous System Across Species
		10.1 ClC-2
			10.1.1 Structure and Function
			10.1.2 ClC-2 in the Vertebrate Brain
			10.1.3 Insights into the Function of Glial ClC Channels from Studies in Invertebrates
		10.2 Acid and Swelling-Activated Cl- Channels (LRRC8 or SWELL1)
		10.3 Acid-Sensitive Outwardly Rectifying (ASOR) Anion Channels
		10.4 Maxi Chloride Channels
		10.5 Pannexins as Cl- Channels
			10.5.1 Structure and Function
			10.5.2 Pannexins in the Nervous System of Vertebrates
			10.5.3 Invertebrate Innexins
		10.6 Bestrophins
			10.6.1 Structure and Function
			10.6.2 Bestrophins in the Mammalian Nervous System
			10.6.3 Bestrophins in Invertebrates
		References
	Chapter 11: Physiological and Pathological Relevance of Selective and Nonselective Ca2+ Channels in Skeletal and Cardiac Muscle
		11.1 Introduction
		11.2 L-Type Ca2+ Channels and Ryanodine Receptors form the Core Functional Unit of Excitation-Contraction Coupling
		11.3 Ca2+ Permeation Through Voltage-Insensitive Channels Is Altered in Striated Muscle Under Pathological States
		References
	Chapter 12: TRPV1 in Pain and Itch
		12.1 Introduction
		12.2 TRPV1 Biology in Pain and Itch
			12.2.1 The Basics of Pain and Itch
			12.2.2 TRPV1 and TRPV1+ Sensory Neurons
			12.2.3 TRPV1 in Pain Sensation
				12.2.3.1 Pain Classification
				12.2.3.2 TRPV1 Serves as the Sensor for Pain Sensation
				12.2.3.3 TRPV1+ Sensory Neuron in Pain Sensation
				12.2.3.4 TRPV1-TRPA1 Complex in Pain Sensation
			12.2.4 TRPV1 in Itch Sensation
				12.2.4.1 Itch Is a Distinct Neural Process from Pain
				12.2.4.2 TRPV1+ Sensory Neuron in Itch Sensation
				12.2.4.3 Role of TRPV1 Ion Channel for Itch Signaling
		12.3 TRPV1 Activity Modulation in Pain and Itch
			12.3.1 TRPV1 Upregulation in the Context of Pain
			12.3.2 TRPV1 Upregulation in the Context of Chronic Itch
			12.3.3 TRPV1 Structure Modulation
			12.3.4 TRPV1 Phosphorylation
				12.3.4.1 PKC Pathway
				12.3.4.2 PKA Pathway
				12.3.4.3 CaMKII-Dependent Phosphorylation
			12.3.5 Other Modulators
				12.3.5.1 Protons
				12.3.5.2 Pirt
				12.3.5.3 GABA-Autocrine Feedback
			12.3.6 Pain-to-Itch Switch
		12.4 TRPV1+ Neurons as the Center of Neuroimmune Interactions
			12.4.1 Mast Cells: A Classic Neuroimmune Paradigm
			12.4.2 Beyond Mast Cells: Other Immune Cells Regulated by Nociceptors
		12.5 Therapeutic Strategy and Perspectives
			12.5.1 Agonist
			12.5.2 Antagonist
			12.5.3 TRPV1 Activity-Dependent Silencing by QX-314
		12.6 Summary
		References
	Chapter 13: Lysosomal TRPML1 Channel: Implications in Cardiovascular and Kidney Diseases
		13.1 Introduction
		13.2 Characteristics of Lysosomal TRPML1 Channels
			13.2.1 Subcellular Localization of Mammalian TRPML1 Channels
			13.2.2 Biophysical Properties of TRPML1 Channels
		13.3 Agonists and Blockers of TRPML1 Channel
			13.3.1 NAADP
			13.3.2 Phosphoinositides
			13.3.3 Synthetic Agonists and Blockers
		13.4 Associated Proteins of TRPML1 Channel
			13.4.1 ALG-2
			13.4.2 Hsc70
			13.4.3 LAPTM
		13.5 Regulatory Mechanisms of TRPML1 Channel Activity
			13.5.1 Cathepsin B
			13.5.2 TOR-TFEB Signaling Pathway
			13.5.3 Phosphorylation
			13.5.4 Regulation of TRPML1 Channel Activity by Sphingolipids
			13.5.5 Redox Regulation of TRPML1 Channel Activity
		13.6 Functions of TRPML1 Channels in Health and Diseases
			13.6.1 Lysosomal pH Control
			13.6.2 Fusion and Fission of Cell Membrane
			13.6.3 Autophagy
			13.6.4 Lysosomal Exocytosis
			13.6.5 Mitochondrial Function
			13.6.6 Triggering of Large Ca2+ Release from Sarcoplasmic Reticulum
			13.6.7 Podocyte Differentiation and Podocytopathy
			13.6.8 Exosome Release and Arterial Medial Calcification
			13.6.9 Lysosome-Mediated Autophagic Flux and Atherogenesis
		13.7 Concluding Remarks
		References
	Chapter 14: Store-Operated Calcium Entry in the Cardiovascular System
		14.1 Introduction
		14.2 Cardiac Excitation-Contraction Coupling
		14.3 Expression of SOCE Components in the Heart
			14.3.1 STIM
			14.3.2 ORAI
			14.3.3 TRPC
		14.4 SOCE During Cardiac Development
		14.5 SOCE in the Vascular System
			14.5.1 SOCE in Vascular Smooth Muscle Cells
			14.5.2 SOCE in Endothelial Cells
			14.5.3 SOCE and Vascular Diseases
				14.5.3.1 Thrombosis
				14.5.3.2 Restenosis
				14.5.3.3 Atherosclerosis
				14.5.3.4 Systemic Arterial Hypertension
				14.5.3.5 Pulmonary Arterial Hypertension
		14.6 SOCE and Cardiac Diseases (see Table 14.1)
			14.6.1 Cardiac Hypertrophy and Heart Failure
			14.6.2 Arrhythmias
		References
	Chapter 15: Physiological Functions, Biophysical Properties, and Regulation of KCNQ1 (KV7.1) Potassium Channels
		15.1 Introduction
		15.2 Physiological Roles for KV7.1 and IKs Channels
		15.3 KV7.1 and KCNQ1/KCNEx Channel Biophysics
		15.4 KV7.1 Channel Structure
		15.5 KCNQ1 Channel Pharmacology
		15.6 KCNQ1 Channel Regulation
		15.7 KCNQ1 and Disease
			15.7.1 Cardiac Arrhythmias
			15.7.2 Diabetes and Cancer
		References
	16: The Role of Thermosensitive Ion Channels in Mammalian Thermoregulation
		16.1 Introduction
		16.2 The Organization of the Thermoregulatory Circuits
			16.2.1 Thermal Afferent Pathways
			16.2.2 Efferent Pathways Controlling Thermoeffectors
		16.3 Thermosensitive Ion Channels and Their Functions in Thermoregulation
			16.3.1 Thermosensitive Properties of the Ion Channels
				16.3.1.1 TRP Channels
					TRPM8
					TRPA1
					TRPC5
					TRPV1
					TRPV2
					TRPV3
					TRPV4
					TRPM2
					TRPM3
				16.3.1.2 TREK Channels
				16.3.1.3 ANO1 (TMEM16A)
				16.3.1.4 STIM1-ORAI1 Channel Complex
		16.4 Summary
		References
	Chapter 17: Mechanotransduction Ion Channels in Hearing and Touch
		17.1 Introduction
		17.2 Mechanosensitive Ion Channels in Touch Sensation
			17.2.1 NOMPC in Gentle Touch Sensation
			17.2.2 Mechanogating Mechanism of NOMPC
			17.2.3 Drosophila Brv1 in Light Touch Sensation
		17.3 Mammalian TMCs in Hearing
			17.3.1 Molecular Components of MET Channels in Hair Cells
			17.3.2 Evidence Supporting TMC as Pore-Forming Subunit of the MET Channel
			17.3.3 Recent Evidence for TMC as a Mechanosensitive Channel
		17.4 Conclusions and Perspectives
		References
	Chapter 18: The Functional Properties, Physiological Roles, Channelopathy and Pharmacological Characteristics of the Slack (KC...
		18.1 The Slack Channel (Slo2.2, KCNT1, KCa4.1)
		18.2 Structural and Functional Domains of Slack Channels
		18.3 The Phosphorylation Modulation on the Gating and Membrane Expression of the Slack Channel
		18.4 The Expression Patterns and Physiological Function of the Slack Channel
		18.5 The Role of the Slack Channel in Pain and Itch Sensing
		18.6 The Possible Role of Slack Channel in FMRP Syndrome
		18.7 The Basic Role of the Potassium Channel in Controlling Neuron Excitability
		18.8 The Potential Roles of Slack Channel in Auditory Signal Transduction
		18.9 The Role of KCNT1 Channel Mutations in Epilepsy
		18.10 The Pharmacological Properties of the KCNT1 Channel and Potential Drugs for the Treatment of Epilepsy That Are Associate...
		18.11 Conclusive Remarks
		References
	Chapter 19: Ion Channels in Anesthesia
		19.1 GABAA Receptor
		19.2 Cholinergic Receptor
		19.3 Glutamate Receptor
		19.4 Two-Pore-Domain Background K+ Channel
		19.5 Conclusion
		References