Studies of Epithelial Transporters and Ion Channels: Ion Channels and Transporters of Epithelia in Health and Disease - Vol. 3 (Physiology in Health and Disease)

Preface to Second Edition-Volume 3
	Volume 3: Studies of Epithelial Transporters and Ion Channels
Preface
Contents
About the Editors
Chapter 1: Na+/K+-ATPase Drives Most Asymmetric Transports and Modulates the Phenotype of Epithelial Cells
	1.1 Introduction
	1.2 It All Started with Émile Du Bois Raymond
	1.3 Polarized Distribution of Na+/K+-ATPase in Epithelial Cells
		1.3.1 Why Do Epithelial Cells Express Na+/K+-ATPase in a Polarized Manner?
		1.3.2 Cues Leading to a Model of Na+/K+-ATPase Polarity
	1.4 Structural Insights into the Na+/K+-ATPase Adhesion Mechanism
	1.5 Cardiac Steroids
		1.5.1 The Search for the Physiological Role of Hormone Ouabain
		1.5.2 Ouabain Modulates the Tight Junction
		1.5.3 Ouabain Modulates Adherens Junctions
		1.5.4 Ouabain Stimulates Ciliogenesis
		1.5.5 Ouabain Modulates Cell-Cell Communication Through Gap Junctions
		1.5.6 Ouabain Modulates the Epithelial Transporting Phenotype
		1.5.7 Na+/K+-ATPase Is a Receptor of Cardiac Steroids
	1.6 Signaling Pathways
	1.7 Pathologies Related to Na+/K+-ATPase
	1.8 Horizons and Perspectives
	References
Chapter 2: Na+-K+-2Cl- Cotransporter
	2.1 Introduction
	2.2 Ouabain-Insensitive Cation Pump?
	2.3 Electrically Silent Plasma Membrane Cotransporters
	2.4 NKCC1
		2.4.1 Electroneutrality, Stoichiometry, and Kinetic Properties
		2.4.2 NKCC1 in Cl- Secreting Epithelia
		2.4.3 NKCC1 in Kidney
		2.4.4 NKCC1 in Other Epithelia
		2.4.5 NKCC1 in Non-epithelial Cells
		2.4.6 NKCC1 in Disease
	2.5 NKCC2
		2.5.1 NKCC2 in Intestine
		2.5.2 NKCC2 in Disease
	2.6 NKCC Activity Is Regulated by Phosphorylation
	2.7 Gene Structure, Cotransporter Family, and Super Family
	2.8 Summary
	References
	Selected Readings
Chapter 3: Thiazide-Sensitive NaCl Cotransporter
	3.1 Introduction
	3.2 Early Studies and Cloning of NCC
	3.3 Primary Structure and Molecular Architecture
	3.4 NCC Transport Characteristics
	3.5 NCC Biogenesis
		3.5.1 NCC Processing in the ER
		3.5.2 Post-ER Processing and Endosomal Storage of NCC
	3.6 NCC Activity at the Plasma Membrane
		3.6.1 NCC Phosphorylation
		3.6.2 The WNK-SPAK/OSR1 Signaling Pathway
			3.6.2.1 SPAK and OSR1
			3.6.2.2 WNK Kinases
				3.6.2.2.1 WNK4
				3.6.2.2.2 WNK1
				3.6.2.2.3 WNK3
		3.6.3 NCC Dephosphorylation by Protein Phosphatases
	3.7 NCC Endocytosis
	3.8 Mendelian Disorders of NCC Dysfunction
		3.8.1 Gitelman Syndrome
		3.8.2 Familial Hyperkalemic Hypertension
	3.9 Physiologic Regulation of NCC
		3.9.1 Regulation by Intracellular Chloride
		3.9.2 Regulation by Extracellular Potassium
		3.9.3 Luminal NaCl Delivery
		3.9.4 Hormonal Regulation of NCC
			3.9.4.1 Angiotensin II
			3.9.4.2 Adrenal Steroids
			3.9.4.3 Gonadal Steroids and NCC
			3.9.4.4 Vasopressin
			3.9.4.5 Insulin
	3.10 Concluding Remarks
	References
Chapter 4: NBCe1: An Electrogenic Na+ Bicarbonate Cotransporter, in Epithelia
	4.1 Introduction
	4.2 Structure of NBCe1
		4.2.1 General Features
		4.2.2 NBCe1 Isoforms
		4.2.3 Structural Features of the N-Terminal Domain
		4.2.4 Structural Features of the Transmembrane Domain
		4.2.5 Structural Features of the C-Terminal Domain
	4.3 Biophysics of NBCe1
		4.3.1 Electrogenicity
		4.3.2 Na+ Dependence
		4.3.3 HCO3- Dependence
		4.3.4 Pharmacological Profile
	4.4 NBCe1 in Health and Disease
		4.4.1 Systemic: Proximal Renal Tubular Acidosis (pRTA)
		4.4.2 The Kidney: Acidemia
		4.4.3 The Eye: Ocular Abnormalities
		4.4.4 The Enamel Organ: Hypomineralized Enamel
		4.4.5 The Pancreas: Elevated Serum Amylase Levels
		4.4.6 The Intestinal Tract: Blockage and Nutritional Deficits
	4.5 The Genetic Basis of NBCe1-Linked Disease
		4.5.1 Human Disease
		4.5.2 Mouse Models
	4.6 Regulation of NBCe1
		4.6.1 General Comments
		4.6.2 Autoregulation: NBCe1-A Versus NBCe1-B/C
		4.6.3 Modulating NBCe1 to Control Renal HCO3- Reabsorption
		4.6.4 Modulating NBCe1 to Control Intestinal HCO3- Secretion
	4.7 Conclusion
	References
Chapter 5: Na+/H+ Exchangers in Epithelia
	5.1 Introduction
	5.2 Classification and Phylogeny of Na+/H+ Antiporters
	5.3 General Features of Epithelial Na+/H+ Exchangers
		5.3.1 Membrane Topology and Functional Domains
		5.3.2 Energy Dependency
		5.3.3 Sensitivity to Inhibitors
	5.4 CPA1/SLC9A: NHE1
		5.4.1 Tissue Specificity and Subcellular Distribution
		5.4.2 Physiological Roles
			5.4.2.1 NHE1 in Epithelial Cell Adhesion and Migration
			5.4.2.2 NHE1 in Epithelial Cell Cycle Regulation and Proliferation
			5.4.2.3 NHE1 in Epithelial Cell Survival and Apoptosis
			5.4.2.4 NHE1 in Epithelial Cell Mechanosensation
		5.4.3 Physiological Regulation
			5.4.3.1 pH Sensing
			5.4.3.2 Phosphorylation
			5.4.3.3 Endocytosis
			5.4.3.4 Transcriptional Regulation
	5.5 CPA1/SLC9A: NHE2
		5.5.1 Tissue Specificity
		5.5.2 Subcellular Distribution
		5.5.3 Physiological Regulation
			5.5.3.1 Developmental Regulation
			5.5.3.2 Tissue-Specific Transcriptional Regulation
			5.5.3.3 Hormonal Regulation
			5.5.3.4 Regulation by Osmolarity
			5.5.3.5 Posttranscriptional Regulation
		5.5.4 Physiological Roles of NHE2: Lessons from Knockout Studies
			5.5.4.1 Role of NHE2 in the Salivary Gland Epithelium
			5.5.4.2 Gastric Epithelium
			5.5.4.3 Intestinal and Colonic Epithelium
			5.5.4.4 Pancreas
			5.5.4.5 Gallbladder Epithelium
			5.5.4.6 Renal Epithelium
		5.5.5 Role of NHE2 in Disease States
	5.6 CPA1/SLC9A: NHE3
		5.6.1 Tissue Specificity
		5.6.2 Subcellular Distribution
		5.6.3 Physiological Regulation
			5.6.3.1 Developmental Regulation
			5.6.3.2 Transcriptional Regulation
			5.6.3.3 Hormonal Regulation of Epithelial NHE3
			5.6.3.4 NHE3 Regulation by Short-Chain Fatty Acids
			5.6.3.5 Serotonin
			5.6.3.6 Metabolic Acidosis
			5.6.3.7 Intestinal Resection
			5.6.3.8 Posttranscriptional Regulation of NHE3
				5.6.3.8.1 Role of Glycosylation in Regulation of NHE3 Activity
				5.6.3.8.2 Regulation of NHE3 Activity by Endosomal Recycling
				5.6.3.8.3 Regulation of NHE3 Activity by Cyclic Nucleotides
				5.6.3.8.4 NHE3 Regulation Via Association with the Cytoskeleton
		5.6.4 Physiological Roles of NHE3: Lessons from Knockout Studies
			5.6.4.1 Intestinal and Colonic Epithelium
			5.6.4.2 Renal Tubular Epithelium
		5.6.5 Role of NHE3 in Disease States
			5.6.5.1 Congenital Sodium Diarrhea (CSD)
			5.6.5.2 Infectious Diarrhea
			5.6.5.3 Inflammatory Bowel Diseases
			5.6.5.4 Diabetic Diarrhea
	5.7 CPA1/SLC9A: NHE4
		5.7.1 Tissue Specificity
		5.7.2 Subcellular Distribution
		5.7.3 Physiological Regulation
		5.7.4 Physiological Relevance/Gene Targeting Studies
		5.7.5 Role of NHE4 in Disease States
	5.8 CPA1/SLC9A: NHE5
	5.9 CPA1/SLC9A: NHE6
		5.9.1 Tissue Specificity
		5.9.2 Subcellular Distribution
		5.9.3 Physiological Relevance/Gene Targeting Studies
		5.9.4 Role of NHE6 in Disease States
	5.10 CPA1/SLC9A: NHE7
		5.10.1 Tissue Specificity
		5.10.2 Subcellular Distribution
		5.10.3 Physiological Regulation
		5.10.4 Physiological Relevance/Gene Targeting Studies
		5.10.5 Role of NHE7 in Disease States
	5.11 CPA1/SLC9A: NHE8
		5.11.1 Tissue Specificity
		5.11.2 Subcellular Distribution
		5.11.3 Physiological Regulation
			5.11.3.1 Developmental Regulation of Epithelial NHE8
			5.11.3.2 Hormonal Regulation of Epithelial NHE8
			5.11.3.3 NHE8 Regulation by SCFAs
		5.11.4 Physiological Relevance/Gene Targeting Studies
			5.11.4.1 NHE8 Contributes to Mucosal Protection in the Gut
			5.11.4.2 Role of NHE8 in the Ocular Epithelium
			5.11.4.3 Role of NHE8 in the Male Reproductive System
		5.11.5 Role of NHE8 in Disease States
	5.12 CPA1/SLC9B: NHA1 and NHA2
	5.13 Other Epithelial Members of CPA1 Family
	5.14 CPA2 Family: Transmembrane and Coiled-Coil Domain 3 (TMCO3)
	5.15 Conclusions
	References
Chapter 6: Sugar Transport Across Epithelia
	6.1 Introduction
	6.2 Gluts
		6.2.1 Introduction
		6.2.2 Cloning
		6.2.3 Structure
		6.2.4 Inhibitors
		6.2.5 Summary
	6.3 SGLTs
		6.3.1 Introduction
		6.3.2 Cloning of the SGLTs
		6.3.3 Kinetics of Sodium-Glucose Cotransport
			6.3.3.1 SGLT1 Capacitive Currents
			6.3.3.2 Theory for hSGLT1 Capacitive Currents
			6.3.3.3 Presteady State Kinetics of W291C-SGLT1
			6.3.3.4 Analysis of Models of SGLT1 Transport
		6.3.4 SGLT2
		6.3.5 Structure
			6.3.5.1 Inhibitors
	6.4 Intestinal and Renal Glucose Transport
		6.4.1 Intestine
		6.4.2 Kidney
	6.5 Conclusions
		6.5.1 Similarities and Differences Between GLUTs and SGLTs
		6.5.2 Epithelial Sugar Transport
	References
Chapter 7: Amino Acid Transporters of Epithelia
	7.1 Introduction
	7.2 Epithelia Lining the Outside of the Body and Amino Acid Transport
		7.2.1 Respiratory Tract
		7.2.2 Gastrointestinal Tract
		7.2.3 Urinary Tract
		7.2.4 Reproductive Tract
		7.2.5 Exocrine Gland Epithelial Cells
		7.2.6 Mammary Gland
	7.3 Examples of Epithelia Constituting Barriers Between Body Compartments
		7.3.1 Barriers Formed by Endothelia
	7.4 Amino Acid Transporters in Exocrine Pancreas
		7.4.1 Origin, Structure, and Function of the Exocrine Pancreas
		7.4.2 Pancreatic Juice
		7.4.3 Amino Acid Import into Acinar Cells
		7.4.4 Neutral Amino Acids Transporters of Acinar Cells
		7.4.5 Cationic Amino Acids Transporters of Acinar Cells
		7.4.6 Anionic Amino Acid Transporters of Acinar Cells
		7.4.7 Regulation of Acinar Cell Amino Acid Transporters by Diet
		7.4.8 Regulation of Amino Acid Transporters in Acinar Cells After Acute Injury
	7.5 Transepithelial Amino Acid Transport Machinery of Small Intestine and Kidney Proximal Tubule
		7.5.1 Luminal Amino Acid Transport of Epithelia
		7.5.2 Basolateral Amino Acid Transport of Epithelia
	7.6 Small Intestine
		7.6.1 Gastrointestinal Tract Origin and Formation
		7.6.2 Intestinal Cell Populations and Their Role
		7.6.3 Intestinal Nutrient Absorption
		7.6.4 Regulation of Small Intestine Amino Acid Transporters
		7.6.5 Apical Amino Acid Transporters of Small Intestine
			7.6.5.1 B0AT1 (SLC6A19)
			7.6.5.2 SIT1 (SLC6A20)
			7.6.5.3 ATB0,+ (SLC6A14)
			7.6.5.4 PAT1 (SLC36A1)
			7.6.5.5 ASCT2 (SLC1A5)
			7.6.5.6 EAAT3 (EAAC1, SLC1A1)
			7.6.5.7 b0,+AT (SLC7A9)
		7.6.6 Basolateral Amino Acid Transporters of Small Intestine
		7.6.7 Basolateral Antiporters of Small Intestine
			7.6.7.1 LAT2-4F2hc (SLC7A8-SLC3A2)
			7.6.7.2 y+LAT1-4F2hc (SLC7A7-SLC3A2) and y+LAT2-4F2hc (SLC7A6-SLC3A2)
		7.6.8 Basolateral Uniporters of Small Intestine
			7.6.8.1 LAT4 (SLC43A2)
			7.6.8.2 TAT1 (SLC16A10)
			7.6.8.3 CAT-1 (SLC7A1)
		7.6.9 Basolateral Symporters of Small Intestine
			7.6.9.1 SNAT2 (SLC38A2)
			7.6.9.2 SNAT5 (SLC38A5)
		7.6.10 Amino Acids Transporters in the Crypts of the Small Intestine
	7.7 Renal Reabsorption of Amino Acids Across the Proximal Tubule
		7.7.1 Amino Acid Transporters of Proximal Kidney Tubule Not Expressed in Small Intestine
			7.7.1.1 PEPT2 (SLC15A2)
			7.7.1.2 B0AT3 (SLC6A18)
			7.7.1.3 PAT2 (SLC36A2)
		7.7.2 Lesson About Basolateral Transporter Cooperation from the Single and Double Transporter Knockout Mice
	7.8 Conclusion
	References
Chapter 8: Structure-Dynamic and Regulatory Specificities of Epithelial Na+/Ca2+ Exchangers
	8.1 Introduction
		8.1.1 NCX as a Ubiquitous System for Ca2+ Extrusion
		8.1.2 Short History of NCX Discovery and Follow-Up Breakthroughs
	8.2 Ca2+ Homeostasis in Epithelial Cells
		8.2.1 Hallmark Features of Ca2+ Homeostasis in Epithelial Cells
		8.2.2 Ca2+ Entry, Buffering, and Exit in Epithelial Cells
		8.2.3 PMCA and NCX Control Ca2+ Extrusion in Mammalian Cells
		8.2.4 Partial Contributions of PMCA and NCX to Ca2+ Extrusion
		8.2.5 Autoregulation Controls the PMCA and NCX Activities
	8.3 NCX-Mediated Ca2+ Entry/Exit in Distinct Cell Types
		8.3.1 Electrogenic Stoichiometry of NCX-Mediated Ion-Exchange
		8.3.2 Forward and Reverse Modes of Na+/Ca2+ Exchange
		8.3.3 Functional Relevance of Ca2+ Flux Directionality Through NCX
	8.4 Genetic Toolbox Shapes Regulatory Assets of NCX Variants
		8.4.1 The NCX Gene Family Is a Branch of the Ca/CA Superfamily
		8.4.2 Common and Distinct Features of NCX Topology Among NCX Variants
		8.4.3 Structure-Related Functional Diversity of Tissues-Specific NCX Variants
		8.4.4 Epithelial NCX Variants
	8.5 Ion-Dependent Regulation of Tissue-Specific NCX Variants
		8.5.1 Allosteric Regulation of NCX Variants by Ca2+, Na+, and H+
		8.5.2 Na+-Dependent Inactivation and Its Alleviation in NCX Variants
		8.5.3 Ca2+-Dependent Activation/Inactivation of NCX Variants
		8.5.4 ``Proton Block´´ and Related Regulatory Modules
	8.6 Structural Basis of Regulatory Diversity in NCX Variants
		8.6.1 High-Resolution Structures of CBD1 and CBD2 Domains
		8.6.2 Structure-Functional Assignments of Ca2+Binding Sites at CBDs
		8.6.3 Exon-Related Modification of Structure-Dynamic Features
		8.6.4 Synergistic Interactions Between the CBD1 and CBD2 Domains
	8.7 Conformational Dynamics of CBDs Are Characteristic Among NCX Variants
		8.7.1 An Interdomain Linker Governs the Dynamic Coupling of CBDs
		8.7.2 Structural Bases for Positive, Negative, or no Response to Regulatory Ca2+
		8.7.3 Ca2+-Driven Tethering of CBDs Rigidifies the CBDs Movements
		8.7.4 The ``Population Shift´´ Mechanism Underlies the Dynamic Coupling of CBDs
		8.7.5 The Functional Relevance of CBDs Dynamic Coupling in NCXs
	8.8 Conclusions
	References
Chapter 9: Urea Transporters in Health and Disease
	9.1 Introduction
	9.2 Regulation of Urea Transporters
		9.2.1 Urea Transporters
	9.3 Membrane Association and Transporter Activity
		9.3.1 Trafficking and Insertion of UT-A1
			9.3.1.1 Regulation by Vasopressin
			9.3.1.2 Regulation by Hyperosmolality
			9.3.1.3 Regulation by Other Factors
		9.3.2 Membrane Association and Activation
		9.3.3 Membrane Removal and Degradation
	9.4 Inner Medullary Architecture and Urea Transport
	9.5 UT-B
		9.5.1 Functional Role of UT-B
		9.5.2 Localization of UT-B
			9.5.2.1 Kidney
			9.5.2.2 Bladder
			9.5.2.3 Gastrointestinal Tract/Rumen
			9.5.2.4 Choroid Plexus
	9.6 Urea Transporter Structure
	9.7 Active Urea Transport
	9.8 Regulation of Urea Transporters in Health (Normal Physiology)
		9.8.1 Adrenal Steroids
		9.8.2 Angiotensin II
		9.8.3 Glucagon
		9.8.4 Aging
	9.9 Therapies Involving Urea Transport Inhibitors (Urearetics)
	9.10 Urea Transporter Responses in Disease (Pathophysiology)
		9.10.1 Diabetes Mellitus Type 1
		9.10.2 Diabetes Mellitus Type 2
		9.10.3 Lithium
		9.10.4 Hypertension
	9.11 Urea Transporter Responses in Renal Disease Models
		9.11.1 Nephrotic Syndrome
		9.11.2 Calcineurin Inhibitors
		9.11.3 Ureteral Obstruction
		9.11.4 Chloroquine
		9.11.5 Sepsis
		9.11.6 Hepatorenal Syndrome
		9.11.7 Uremia
		9.11.8 Bladder Cancer
	9.12 Genetic Ablation of Urea Transporters
		9.12.1 UT-B Knock-Out Mice
		9.12.2 UT-A2 and UT-B/UT-A2 Knock-Out Mice
		9.12.3 UT-A1/UT-A3 and UT-A3 Knock-Out Mice
		9.12.4 All UT Knock-Out Mice
	9.13 Conclusions
	References
Chapter 10: H,K-ATPases in Epithelia
	10.1 Introduction
		10.1.1 The Family of P-Type ATPases
		10.1.2 H,K-ATPases
		10.1.3 Different H,K-ATPases for Different Physiological Functions
	10.2 H,K-ATPase Type 1 (Atp4a)
		10.2.1 Generality
		10.2.2 Pharmacological Properties
		10.2.3 Physiological Roles
			10.2.3.1 Acidification of the Gastric Fluid
			10.2.3.2 Renal Function of HKA1
			10.2.3.3 HKA1 and Embryonic Development
	10.3 H,K-ATPase Type 2 (Atp12a)
		10.3.1 Generality
		10.3.2 Pharmacological Properties of HKA2
		10.3.3 Physiological Roles of HKA2
			10.3.3.1 HKA2 and K+ Balance
			10.3.3.2 HKA2 and Na+ Balance
			10.3.3.3 HKA2 in Prostate
			10.3.3.4 HKA2 in Pancreas
			10.3.3.5 HKA2 in Airway Epithelium
	10.4 Conclusions
	References
Chapter 11: Zinc Transporters Involved in Vectorial Zinc Transport in Intestinal Epithelial Cells
	11.1 Introduction
	11.2 Zinc Import into Enterocytes Across the Apical Membrane
	11.3 Zinc Release from Enterocytes Across the Basolateral Membrane
	11.4 Transepithelial Transport of Zinc in Enterocytes
	11.5 Other Zinc Transporters Possibly Involved in Zinc Absorption
	11.6 Vectorial Transport of Other Trace Elements
		11.6.1 Iron Transport in the Enterocytes
		11.6.2 Copper Transport in the Enterocytes
		11.6.3 Manganese Transport in the Enterocytes
	11.7 Conclusions
	References
Chapter 12: Properties, Structure, and Function of the Solute Carrier 26 Family of Anion Transporters
	12.1 General Features of the SLC26 Transporters
		12.1.1 Structure of the SLC26 Transporters
		12.1.2 Regulation of the SLC26 Transporters
		12.1.3 Cl- Sensing by SLC26 Transporters
	12.2 Transport Properties of the SLC26 Transporters
		12.2.1 The SO42- Transporters
		12.2.2 The Anion Exchangers
		12.2.3 The Anion Channels
	12.3 Conclusion
	References
Chapter 13: ClC-2 Chloride Channels
	13.1 Introduction
	13.2 Review Articles
	13.3 The Beginning: ClC-0
	13.4 Properties of Rat ClC-2
		13.4.1 Cloned Rat ClC-2
		13.4.2 ClC-2 in the Rat Airway
		13.4.3 Cloned Human ClC-2
	13.5 Single-Channel Studies of ClC-2
	13.6 Single-Channel Studies of ClC-2 in the Presence of CFTR and Other Cl- Channels
	13.7 PKA Phosphorylation of ClC-2
	13.8 Small-Molecule Activators of ClC-2
		13.8.1 Protons
		13.8.2 ATP
		13.8.3 Activation by Fatty Acids and Lubiprostone
			13.8.3.1 Lubiprostone Stimulation of Recombinant ClC-2
			13.8.3.2 Lubiprostone Activation in Cell Lines Containing Both ClC-2 and CFTR
			13.8.3.3 Site of Action of Lubiprostone in Stimulation of ClC-2
			13.8.3.4 Lubiprostone Stimulation of Recombinant ClC-2 from Other Species
			13.8.3.5 Lack of Involvement of PKA Phosphorylation in Lubiprostone Stimulation
			13.8.3.6 Identification of Possible Fatty Acid Binding Site on Human ClC-2
	13.9 ClC-2 Function in Epithelia
	13.10 Lubiprostone in Human Treatments
		13.10.1 Chronic Idiopathic Constipation, Irritable Bowel Syndrome, and Opioid-Induced Constipation
		13.10.2 Effect of Lubiprostone in the Intestine of CF Patients
	13.11 Lubiprostone Is Not an EP4 Receptor Agonist: Rather, It Is an EP4 Receptor Antagonist
	13.12 H-89 Effects
	13.13 Small-Molecule Effectors
		13.13.1 Compounds That May Be Useful for Studies of ClC-2 in the Presence of CFTR and Other Cl- Channels
		13.13.2 Compounds That May Not Be Useful for Studies of ClC-2 in the Presence of CFTR and Other Cl- Channels
	13.14 Summary
	References
Chapter 14: The Role of the Endosomal Chloride/Proton Antiporter ClC-5 in Proximal Tubule Endocytosis and Kidney Physiology
	14.1 Introduction
		14.1.1 The Physiological Relevance of Chloride Transport
		14.1.2 The CLC Protein Family
	14.2 Structures of CLC Channels and Transporters
		14.2.1 Proton Transport
		14.2.2 CBS (Cystathionine Beta Synthase) Cytoplasmic Domains of ClC-5
	14.3 Gating
		14.3.1 Gating Mechanism in the CLC Transporters
	14.4 Transport Mechanism
		14.4.1 Stoichiometry
		14.4.2 Transport Cycle
	14.5 Role of ClC-5 in Endosomal Physiology and Kidney Function
		14.5.1 ClC-5 Localization in Renal Epithelia
		14.5.2 Sorting and Degradation Processes of ClC-5
		14.5.3 ClC-5 and Dent´s Disease
		14.5.4 ClC-5 Knockout Mice Reveal Dent´s Disease Mechanism
			14.5.4.1 Proteinuria
			14.5.4.2 Hypercalciuria
			14.5.4.3 Night Blindness
			14.5.4.4 Hyperphosphaturia
			14.5.4.5 Altered Ion and Water Absorption
		14.5.5 Potential Binding Partner of ClC-5
		14.5.6 ClC-5 Mutations and Their Phenotypes
		14.5.7 ClC-5 Mutations in Patient-Derived Cells Reveal Altered Endocytosis Without Effects on Endosomal Acidification
	14.6 Other Proteins Involved in Dent´s Disease
	14.7 Summary
	References
Chapter 15: CFTR and Cystic Fibrosis: A Need for Personalized Medicine
	15.1 Introduction
	15.2 Biology of CFTR
	15.3 Clinical Manifestations of CFTR Mutations
	15.4 Symptom-Based CF Therapies
	15.5 Classification of CFTR Mutations
		15.5.1 Class I Mutations Prevent the Production of Full-Length CFTR
		15.5.2 Class II Mutations Alter the Intracellular Processing of CFTR
		15.5.3 Class III Mutations Alter CFTR Channel Regulation
		15.5.4 Class IV Mutations Alter CFTR Channel Conductance
		15.5.5 Class V Mutations Alter the Amount of Functional CFTR Protein
		15.5.6 Class VI Mutations Alter Surface Retention
		15.5.7 Multi-class Mutations
	15.6 CFTR Mutants: What Needs to Be Fixed?
	15.7 Personalized Medicine, Bespoke Treatments, Precision Medicine, and Theratyping
	15.8 Creating Drugs to Treat the Basic Defect in Cystic Fibrosis
		15.8.1 Nucleic Acid Approaches
		15.8.2 Pharmacologic Approaches
		15.8.3 Suppressors of Premature Termination: Making More CFTR
		15.8.4 CFTR Potentiators: Opening a Sticky Gate
			15.8.4.1 Ivacaftor (VX-770, Kalydeco)
			15.8.4.2 CTP-656
			15.8.4.3 GLPG1837
			15.8.4.4 QBW251
			15.8.4.5 Mechanism of Potentiator Action
		15.8.5 CFTR Correctors: Solving Misguided Traffic
			15.8.5.1 FDL169
			15.8.5.2 GLPG2222
			15.8.5.3 Lumacaftor
			15.8.5.4 Tezacaftor (VX-661)
			15.8.5.5 VX-440, VX-152, and VX-659
		15.8.6 How Do Correctors Work?
		15.8.7 Make It a Combo!
			15.8.7.1 ORKAMBI
			15.8.7.2 Tezacaftor/Ivacaftor (Symdeko)
			15.8.7.3 Triple Threat
		15.8.8 Proteostasis Therapeutics
		15.8.9 Galapagos/AbbVie
		15.8.10 Amplifiers
	15.9 Alternative Approaches
		15.9.1 PTI-801 + Orkambi
	15.10 How Much Is Enough?
	15.11 Future Perspectives
	References
Chapter 16: Molecular Physiology and Pharmacology of the Cystic Fibrosis Transmembrane Conductance Regulator
	16.1 Introduction
	16.2 Roles of CFTR in Epithelial Ion Transport and Host Defense
		16.2.1 The Sweat Gland
		16.2.2 The Pancreas, Intestine, Hepatobiliary System, and Reproductive Tissues
		16.2.3 The Respiratory Airways
		16.2.4 The Kidney
	16.3 Molecular Architecture of CFTR
		16.3.1 The Membrane-Spanning Domains
		16.3.2 The Regulatory Domain
		16.3.3 The Nucleotide-Binding Domains
		16.3.4 The Amino and Carboxyl Termini
	16.4 The Gating Pathway of CFTR
		16.4.1 Structural Rearrangement of CFTR Domains Following ATP Binding
		16.4.2 The CFTR Gating Cycle
	16.5 CFTR Biogenesis and Plasma Membrane Expression
	16.6 CFTR Mutations
	16.7 Mutation-Specific Therapies for CF
		16.7.1 CFTR Potentiators
		16.7.2 CFTR Correctors
		16.7.3 Combination Therapy with CFTR Correctors and Potentiators
	16.8 Rescuing the Plasma Membrane Expression of CF Mutants with Proteostasis Regulators
		16.8.1 Constituents of the ER Quality Control Machinery as Possible Drug Targets for F508del-CFTR Rescue
		16.8.2 Heat Shock Proteins and Co-chaperones: Helping CFTR to Fold (or to Degrade?)
		16.8.3 Constituents of the Peripheral Quality Control Machinery as Possible Drug Targets for F508del-CFTR Rescue
	16.9 Conclusion
	References
Chapter 17: TMEM16 Proteins (Anoctamins) in Epithelia
	17.1 General Characteristics of TMEM16 Proteins
	17.2 Regulation of TMEM16A Channel Activity by Ca2+ Signaling
	17.3 Regulation of TMEM16A by PIP2
	17.4 TMEM16A in Airway Surface Epithelial Cells
	17.5 TMEM16A in the Intestine
	17.6 Expression and Function of TMEM16A in Exocrine Glands
	17.7 TMEM16A in Kidney
	17.8 Regulation of TMEM16A Expression
	17.9 Other Functions of TMEM16A
	17.10 TMEM16F and Other Anoctamins in Epithelial Cells
	17.11 Perspectives
	References
Chapter 18: Epithelial Sodium Channels (ENaC)
	18.1 Introduction
		18.1.1 Mechanism of Salt Transport Across Epithelial Tissues
		18.1.2 The Sodium-Selective Entry Pathway Is Blocked by the Diuretic, Amiloride, and Is an Ion Channel
	18.2 Molecular Properties of ENaC
	18.3 Structure of ENaC
		18.3.1 Alternative Structures for ENaC Family Members
	18.4 Cellular Regulation of ENaC
		18.4.1 Small Molecule Agents that Modify ENaC Activity
			18.4.1.1 Amiloride
			18.4.1.2 Ion Activity
				18.4.1.2.1 Sodium Ion Activity
				18.4.1.2.2 Sodium Self-Inhibition
				18.4.1.2.3 Sodium Feedback Inhibition
				18.4.1.2.4 Chloride Ion Activity
				18.4.1.2.5 Hydrogen Ion
				18.4.1.2.6 Calcium Ion Activity
				18.4.1.2.7 Heavy Metal Ions
		18.4.2 Post-Translational Modifications of ENaC
			18.4.2.1 Acetylation
			18.4.2.2 Methylation
			18.4.2.3 Ubiquitination
			18.4.2.4 A Specific Ubiquitin Ligase Isoform, Nedd4-2, Ubiquitinates ENaC
			18.4.2.5 De-ubiquitination of ENaC
			18.4.2.6 Phosphorylation
			18.4.2.7 Proteolysis
			18.4.2.8 ENaC´s Role in Nephrotic Syndrome
		18.4.3 Transmitter and Humoral Agents That Modify ENaC Activity
			18.4.3.1 Regulation of ENaC by Adrenergic Agents
			18.4.3.2 Regulation of ENaC by Vasopressin
			18.4.3.3 Regulation of ENaC by Purinergic Agonists
				18.4.3.3.1 Mechanisms of Apical ATP Release in Epithelia
				18.4.3.3.2 Mechanisms of Basal ATP Release in Epithelia
				18.4.3.3.3 Purinergic Receptor Families
				18.4.3.3.4 Effects of Apical ATP on ENaC in the Kidney
				18.4.3.3.5 Effects of Basolateral ATP on ENaC in the Kidney
				18.4.3.3.6 Effects of ATP on ENaC in Airway
				18.4.3.3.7 ENaC Regulation by Purinergic Receptors in Other Tissues
			18.4.3.4 Regulation of ENaC by Dopamine
			18.4.3.5 Regulation of ENaC by Cholinergic Agonists
			18.4.3.6 Regulation of ENaC by Angiotensin II
			18.4.3.7 Regulation of ENaC by Hydrogen Sulfide
			18.4.3.8 Regulation of ENaC by Sex Hormones
			18.4.3.9 Regulation of ENaC by Reactive Oxygen Species (ROS)
			18.4.3.10 Regulation of ENaC by Nitric Oxide
			18.4.3.11 Interaction of NO and ROS Signaling in ENaC Regulation
			18.4.3.12 Regulation of ENaC by Endothelin
			18.4.3.13 ENaC and Diabetes
		18.4.4 Regulation of ENaC by Pathogens, Cytokines, and Chemokines
			18.4.4.1 Regulation of ENaC by TNF-α
			18.4.4.2 Regulation of ENaC by the Interleukins
			18.4.4.3 Regulation of ENaC Via TGF-β1
			18.4.4.4 Regulation of ENaC by Interferon-γ
			18.4.4.5 Cytokines in the Kidney
	18.5 Regulation of ENaC Density in the Apical Membrane
		18.5.1 ENaC Trafficking to the Apical Membrane
		18.5.2 ENaC Leaves the Apical Membrane
	18.6 An Extended ENaC Regulatory Complex
		18.6.1 The ERC and Regulation of Na Channels by Inositol Lipids
		18.6.2 The Role of MARCKS Protein
		18.6.3 ENaC Is Activated by Cysteine-Palmitoylation
		18.6.4 Role of the Cytoskeleton
	18.7 ENaC Mechanosensitivity
	18.8 ENaC in Endothelial and Vascular Smooth Muscle Cells
	18.9 The Molecular Basis for ENaC Regulation by Aldosterone
		18.9.1 Activate Existing Channels by Increasing Their Open Probability
		18.9.2 Keep Existing (and Any New) ENaC in the Membrane
		18.9.3 Recruit More Active Channels to the Membrane
		18.9.4 Transcribe and Translate New ENaC Subunits
		18.9.5 Regulation of ENaC by MicroRNAs
		18.9.6 Summary
	References
Chapter 19: ROMK and Bartter Syndrome Type 2
	19.1 Introduction
	19.2 The ROMK Channel
	19.3 ROMK Function in the TAL
	19.4 Transient Hyperkalemia, A Unique Phenotype of Bartter Type II
	19.5 Carriers of Bartter Mutations Are Protected from Hypertension
	19.6 Bartter Mutations in ROMK, Overview
	19.7 Bartter Mutations in the Potassium Permeation Structure
	19.8 Bartter Mutations That Alter Regulated Gates
	19.9 Bartter Mutations That Disrupt Channel Modulation
		19.9.1 PIP2
		19.9.2 PKA Phosphorylation Sites
		19.9.3 pH-Dependent Gating
	19.10 Summary
	References
Chapter 20: Inwardly Rectifying K+ Channel 4.1 Regulates Renal K+ Excretion in the Aldosterone-Sensitive Distal Nephron
	20.1 Introduction
	20.2 Kir4.1/Kir5.1 Forms the Basolateral K+ Channel in the ASDN
	20.3 Kir5.1 Is a Regulatory Subunit for Kir4.1/Kir5.1 Heterotetramer
	20.4 Regulation of Kir4.1 and Kir5.1 in the Kidney
	20.5 Kir4.1/Kir5.1 Determines the Membrane Potential of the DCT
	20.6 Regulation of K+ Homeostasis by Kidney and Extrarenal Factors
	20.7 Renal K+ Transport Along the Nephron Segment
		20.7.1 Proximal Convoluted Tubule (PCT)
		20.7.2 Thick Ascending Limb (TAL)
		20.7.3 Distal Convoluted Tubule (DCT)
		20.7.4 Connecting Tubule (CNT) and Cortical Collecting Duct (CCD)
	20.8 NCC Regulates Renal K+ Excretion
	20.9 Role of Kir4.1/Kir5.1 in the Regulation of NCC
	20.10 The Mechanism of Kir4.1 Regulating NCC
	20.11 Kir4.1/Kir5.1 Is Essential for Dietary K+ Intake-Induced Regulation of NCC
	20.12 Signaling in the Regulation of Kir4.1/Kir5.1 and NCC
		20.12.1 Role of AT2R and BK2R in the Regulation of Kir4.1 and NCC
		20.12.2 Role of Kir4.1 in Mediating the Adrenergic Receptor-Induced Stimulation of NCC
	20.13 Kir4.1/Kir5.1 Is Essential for the Effect of Dietary Na+ Intake on NCC
	20.14 Role of Kir4.1/Kir5.1 in Aldosterone Paradox
	20.15 Conclusion Remarks
	References
Chapter 21: Small-Molecule Pharmacology of Epithelial Inward Rectifier Potassium Channels
	21.1 Overview of Inward Rectifier Potassium Channel Structure and Function
	21.2 The Renal Outer Medullary Potassium Channel (ROMK, Kir1.1, KCNJ1)
		21.2.1 Overview of ROMK Expression and Functions in Renal Tubule Epithelia
		21.2.2 Genetic Validation of ROMK as a Diuretic Target
		21.2.3 ROMK Drug Discovery
		21.2.4 ROMK Inhibitor Molecular Mechanisms of Action
	21.3 Kir4.1 (KCNJ10) and Kir4.1/5.1 (KCNJ16)
		21.3.1 Are Kir4.1-Containg Channels Basolateral Membrane Diuretic Targets?
		21.3.2 Genetic Validation of Kir4.1 as a Diuretic Target
		21.3.3 Kir4.1 Pharmacology
	21.4 Kir7.1 (KCNJ13)
		21.4.1 Overview of Kir7.1 Expression and Function
		21.4.2 Kir7.1 Pharmacology
	21.5 Kir2.3 (KCNJ4)
		21.5.1 A Basolateral Channel with no Known Functions
		21.5.2 Kir2.3 Pharmacology
	21.6 Conclusions and Future Perspectives
	References
Chapter 22: KCa3.1 in Epithelia
	22.1 Introduction
		22.1.1 Early Evidence for Ca2+-mediated Regulation of Transepithelial Transport
		22.1.2 Basolateral Membrane Ca2+-activated K+ Channels
	22.2 Cloning of KCa3.1
	22.3 Role of Basolateral KCa3.1 in Transepithelial Ion Transport
		22.3.1 KCa3.1 in the Basolateral Membrane of Intestinal Epithelium
		22.3.2 KCa3.1 in the Basolateral Membrane of Airway Epithelium
		22.3.3 KCa3.1 in the Basolateral Membrane of Salivary Acinar and Pancreatic Duct Epithelium
	22.4 Role of KCa3.1 in the Apical Membrane
	22.5 Gating of KCa3.1
		22.5.1 Structure of KCa3.1
		22.5.2 A Gating Model for KCa3.1
		22.5.3 KCa3.1 Pore Architecture and Allostery
		22.5.4 Role of KCa3.1 in Gating of Maxi-K (KCa1.1)
	22.6 Regulation of KCa3.1
	22.7 Trafficking of KCa3.1
		22.7.1 Anterograde Trafficking of KCa3.1
		22.7.2 Retrograde Trafficking of KCa3.1
		22.7.3 Plasma Membrane Targeting of KCa3.1 in Polarized Cells
	22.8 Role of KCa3.1 in the Cell Cycle, Cell Proliferation, and Cancer Biology
	22.9 Role of KCa3.1 in Disease
		22.9.1 Role of KCa3.1 in Hemolytic Anemia
		22.9.2 Role of KCa3.1 in Epithelial Diseases
	22.10 Conclusions
	References
Chapter 23: BK Channels in Epithelia
	23.1 Introduction
	23.2 BK-Mediated K+ Secretion in Renal Epithelia
	23.3 BK-Mediated K+ Secretion in the Colon
	23.4 BK-Mediated K+ Secretion in Exocrine Glands
	23.5 Pulmonary Epithelia
	23.6 BK in the Basolateral Membranes of Epithelia
	23.7 Summary
	References
Chapter 24: Recent Developments in the Pharmacology of Epithelial Ca2+-Activated K+ Channels
	24.1 Introduction
		24.1.1 KCa Channel Expression and Function in Epithelia
		24.1.2 Basic Properties of KCa1.1 and KCa3.1 Channels
		24.1.3 Basic Pharmacology of KCa1.1 and KCa3.1 Channels
	24.2 KCa1.1 Channel Modulator Chemistry
		24.2.1 KCa1.1 Channel Activators
		24.2.2 KCa1.1 Channel Inhibitors
	24.3 KCa3.1 Channel Modulator Chemistry
		24.3.1 KCa3.1 Channel Activators
		24.3.2 KCa3.1 Channel Inhibitors
	24.4 Interaction Sites for KCa1.1/KCa3.1 Channel Modulators
	24.5 Conclusions and Perspectives
	References
Chapter 25: KCNE Regulation of KCNQ Channels
	25.1 Introduction
		25.1.1 Voltage-Dependent Ion Channel Functional Architecture
		25.1.2 Background to KCNE Proteins
		25.1.3 KCNQ1: The Primary KCNE Partner in Epithelial Biology
	25.2 KCNQ1-KCNE1 Channels in Epithelial Biology
		25.2.1 KCNQ1-KCNE1 in Auditory Epithelium
		25.2.2 The Possible Roles of KCNQ1 and KCNE1 in the Kidneys
	25.3 KCNQ1-KCNE2: Constitutively Active at Hyperpolarized Potentials Despite Its Voltage Sensor
		25.3.1 KCNQ1-KCNE2 in the Gastric Epithelium
		25.3.2 KCNQ1-KCNE2 in the Thyroid Epithelium
		25.3.3 KCNQ1-KCNE2 in the Choroid Plexus Epithelium
		25.3.4 KCNE2 in the Pancreas
	25.4 KCNQ1-KCNE3: A Highly Studied, Constitutively Active Channel
		25.4.1 KCNQ1-KCNE3 in the Intestinal Epithelium
		25.4.2 KCNQ1-KCNE3 in the Mammary Epithelium
		25.4.3 KCNQ1-KCNE3 in the Airway Epithelium
	25.5 Epithelial Roles for KCNE4
		25.5.1 KCNE4 in the Kidney
		25.5.2 KCNE4 in the Uterus
	25.6 Trafficking of KCNQ1-KCNE Channel Complexes
		25.6.1 RAB- and Clathrin-Dependent Trafficking of KCNQ1
		25.6.2 KCNE-Dependent Polarized Trafficking of Epithelial KCNQ1
	25.7 Conclusions
	References
Chapter 26: Orai Channels
	26.1 Introduction
	26.2 Store-Operated CRAC Channels
		26.2.1 Biophysical Properties
		26.2.2 Molecular Identity of the CRAC Channel
		26.2.3 STIM1 and CRAC Channel Activation
		26.2.4 CRAC Channel Gating and Calcium Permeation
	26.3 Store-Independent ARC Channels
		26.3.1 Biophysical Properties
		26.3.2 STIM1 and ARC Channel Activation
		26.3.3 Molecular Basis of ARC Channel Structure
		26.3.4 Molecular Basis for the Selective Activation of ARC Channels
	26.4 Other Orai Channels
	26.5 Physiological Roles of Orai Channels
	26.6 Conclusions
	References
Chapter 27: TRP Channels in Renal Epithelia
	27.1 Introduction
	27.2 Contribution of TRPC3 to Arginine Vasopressin (AVP) Signaling in the Collecting Duct
	27.3 Role of TRPC6/TRPC5 in Glomerular Filtration and Podocyte Function
	27.4 TRPM2 in the Proximal Tubule Exacerbates Ischemia Reperfusion Injury
	27.5 TRPM6/TRPM7 as Mediators of Mg2+ Transport in the Distal Convoluted Tubule
	27.6 TRPV4 and Mechanosensitivity in the Renal Tubule
	27.7 TRPV5/TRPV6 and Renal Ca2+ Handling
	27.8 Conclusions
	References
Chapter 28: P2X Receptors in Epithelia
	28.1 Introduction
	28.2 P2X Receptors and Excitation-Secretion Coupling
	28.3 P2X Receptors in Absorptive Epithelia
	28.4 Identification of the Native P2X Receptor Responsible for a Physiological Response
	28.5 Intracellular Signalling Events Associated with Epithelial P2X Receptor Activation
	28.6 Apical and Basolateral P2X Receptors
	28.7 Epithelial P2X Receptors in Pathophysiology
	28.8 Other Functional Implications of Epithelial P2X Receptors
	28.9 Final Concluding Remarks
	References
Chapter 29: The Polycystins and Polycystic Kidney Disease
	29.1 Discovery of the PKD Genes and the Polycystin Proteins
	29.2 The Functional Importance of the Polycystins: Autosomal Dominant Polycystic Kidney Disease
	29.3 Structure of the Polycystins
		29.3.1 Polycystin 1
		29.3.2 Polycystin 2
		29.3.3 Other Polycystin Isoforms
	29.4 The Polycystin Channels
		29.4.1 The Classic PC1-PC2 Channel
		29.4.2 Alternate Polycystin Channels and Isoforms
		29.4.3 Other Heteromeric Polycystin Channels
		29.4.4 Other Potential Functions of the Polycystins
	29.5 PC1 and PC2 Localization and Binding Partners
		29.5.1 Historical Studies
		29.5.2 Polycystin 1 and 2 Expression in Primary Cilia
		29.5.3 PC1 in the Plasma Membrane and Cell-to-Cell Junctions
		29.5.4 PC1 Interactions with the Extracellular Matrix (ECM)
		29.5.5 Polycystins in ER and Ca2+ Release Channels
		29.5.6 Other Potential Binding Partners
	29.6 Mechanisms Underlying Renal Cystogenesis: Further Clues to Polycystin Function
		29.6.1 Intracellular Signaling Pathways
		29.6.2 Cyst-Filling Fluid Secretion
		29.6.3 Proliferation in Cyst Development
		29.6.4 Role of Metabolism in Cyst Development
		29.6.5 The Importance of Gene Dosage and Developmental Expression of the Polycystins
	29.7 Role of Polycystin in Extra-Renal Pathology
		29.7.1 Liver and Pancreatic Cysts
		29.7.2 Cardiovascular Abnormalities
		29.7.3 Extra-Tubular Renal Expression
	29.8 Closing Remarks
	References
Chapter 30: Renal Aquaporins in Health and Disease
	30.1 Introduction
	30.2 Renal Aquaporins
		30.2.1 Aquaporin 1 (AQP1)
		30.2.2 Aquaporin 2 (AQP2)
		30.2.3 Aquaporin 3 (AQP3)
		30.2.4 Aquaporin 4 (AQP4)
		30.2.5 Aquaporin 5 (AQP5)
		30.2.6 Aquaporin 6 (AQP6)
		30.2.7 Aquaporin 7 (AQP7)
		30.2.8 Aquaporin 8 (AQP8)
		30.2.9 Aquaporin 11 (AQP11)
	30.3 Renal Aquaporins in Disease
		30.3.1 Water Balance Disorders Associated with Hyponatremia and Increased Aquaporin Levels
		30.3.2 Congestive Heart Failure
		30.3.3 Hepatic Cirrhosis
		30.3.4 Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)
		30.3.5 Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD)
	30.4 Treatment of Pathologies Resulting from Increased Aquaporin Levels
		30.4.1 Demeclocycline
		30.4.2 V2R Antagonists
	30.5 Water Balance Disorders Associated with Polyuria and Decreased Aquaporin Levels
		30.5.1 Central Diabete Insipidus (CDI)
		30.5.2 Gestational DI
		30.5.3 Nephrogenic DI
			30.5.3.1 Congenital NDI
			30.5.3.2 Acquired NDI
				30.5.3.2.1 Electrolyte Disorders
				30.5.3.2.2 Obstruction of the Urinary Tract
				30.5.3.2.3 Lithium-Induced NDI
				30.5.3.2.4 Acute Tubulo-Interstitial Nephritis
				30.5.3.2.5 Diabetes Mellitus
	30.6 Treatment of Polyuria
		30.6.1 Diuretics
		30.6.2 Future Therapies
	30.7 Conclusion
	References