The sodium-hydrogen exchanger : from molecule to its role in disease / edited by Morris Karmazyn, Metin Avkiran, Larry Fliegel.

Format:

Book

Contributor:

Karmazyn, M. (Morris), 1950-

Avkiran, M. (Metin)

Fliegel, Larry, 1956-

Language:

English

Subjects (All):

Sodium cotransport systems.

Hydrogen ions--Physiological transport.

Hydrogen ions.

Carrier proteins.

Sodium-Hydrogen Exchangers--physiology.

Cell Cycle Proteins--physiology.

Medical Subjects:

Sodium-Hydrogen Exchangers--physiology.

Cell Cycle Proteins--physiology.

Physical Description:

xxxii, 318 pages : illustrations ; 25 cm

Place of Publication:

Boston : Kluwer Academic Publishers, [2003]

Summary:

This volume contains state-of-the-art reviews dealing with diverse aspects of the sodium-hydrogen exchange family of membrane transporters - from basic science to clinical relevance. *Includes a wide spectrum of topics dealing with sodium-hydrogen exchange ranging from molecular to clinical. *Covers established and emerging concepts related to sodium hydrogen exchange including newly identified novel isoforms. *Updates on completed and continuing clinical trials with sodium-hydrogen exchange inhibitors. The Sodium-Hydrogen Exchanger - From Molecule to its Role in Disease will be of interest to pharmacologists, physiologists, biochemists, cell and molecular biologists and clinical scientists interested in new therapeutic concepts related to sodium-hydrogen exchange inhibition.

Contents:

Chapter 1 Regulation of Intracellular pH in Mammalian Cells

2. Intracellular Compartmentalization Of pH 2

3. Cytoplasmic pH 2

4. Intracellular Buffers 3

5. Measurement Of pH[subscript i] During Acid-Base Loading 5

6. Transport Systems That Regulate pH[subscript i] 5

6.1 NHE 7

6.2 NBC 8

6.3 NDCBE 9

6.4 MCT 9

6.5 H[superscript +]-ATPase 9

6.6 AE And CHE 10

6.7 Other Acid Extruders And Loaders 10

Chapter 2 Molecular and Functional Diversity of Mammalian Na[superscript +]/H[superscript +] Exchangers

2. Genetic Heterogeneity 18

2.1. Structure And Function Relations 20

2.2 Tissue Expression, Subcellular Distribution, And Physiological Roles 22

Chapter 3 Two Functional Regulatory Factors of the Na[superscript +]/H[superscript +] Exchangers The Proton and CHP

2. The Proton 36

2.1 The H[superscript +]-Modifier Site 36

2.2 Critical Regions Involved In pH-Sensing 39

3. CHP 41

3.1 CHPI As An Essential Cofactor 41

3.2 Role Of CHP2 43

Chapter 4 Regulation of Expression of the Na[superscript +]/H[superscript +] Exchanger in the Myocardium and Other Tissues

1.1 The Importance Of pH Regulation And Na[superscript +]/H[superscript +] Exchangers 51

1.2 Other Physiological Roles Of Na[superscript +]/H[superscript +] Exchangers 53

1.3 The Na[superscript +]/H[superscript +] Exchanger And The Myocardium 54

1.4 The Na[superscript +]/H[superscript +] Exchanger In Myocardial Diseases 54

2. Na[superscript +]/H[superscript +] Exchanger Expression Varies In Response To The Environment 55

3. Transcriptional Regulation Of The Na[superscript +]/H[superscript +] Exchanger Gene 57

3.1 The Human, Rabbit And Porcine NHE1 Promotors 57

3.2 Regulation Of The Mouse NHE1 Promoter 58

3.2.1 Proximal Regions Of The Mouse NHE1 Promoter 58

3.2.2 Distal Regions Of The Mouse NHE1 Promoter 59

3.2 Regulation Of The NHE1 Promoter In The Myocardium 60

Chapter 5 Na-H Exchange Function in Colonic Epithelial Cells

2. Apical Membrane NHEs 72

2.1 Cl-dependent NHE In Crypt Cells 77

3. Basolateral Membrane NHEs 83

Chapter 6 NhaA Na[superscript +]/H[superscript +] Antiporter. Structure, Mechanism and Function in Homestasis of Na[superscript +] and pH

2. The Response to Na[superscript +] Occurs At The Transcription Level 92

2.1 Exponential Phase Of Growth 92

2.2 Stationary Phase Cells 92

3. The Ecological Importance Of The Antiporters In The Enteric Bacteria Escherichia Coli And Vibrio Cholerae 93

4. The NhaA Protein 94

4.1 The Structure of NhaA, 2D Crystals 95

On The Way To Atomic Resolution Of NhaA, 3D Crystals 96

4.3 NhaA Is A Dimer In The Membrane 97

4.4 Mapping The Interface Between NhaA Monomers 97

4.5 Proximities Between Helices Of NhaA 98

5. Relationship Between Function And Structure Of NhaA 99

5.1 The pH Response Of NhaA Occurs At The Protein Level 99

5.2 Differentiating Between Residues Involved In The Translocation Pathway And The pH Regulation 99

5.2.1 Mutants Within Putative [alpha] Helices 100

5.2.2 Mutants Within Loops 101

6. Dynamics Of NhaA 101

6.1 The pH Signal Is Transduced In The Protein By A pH Induced Conformational Change 101

6.1.1 Identifying Conformational Changes By Accessibility To Trypsin 101

6.1.2 Identifying Conformational Changes By The Use Of mAbs 102

7. Dynamics In 3D Of The pH Induced Conformational Changes Of NhaA 102

7.1 The pH Induced Conformational Change Of Loop VII-IX Involves The Interface Between NhaA Monomers 102

Chapter 7 The Use of Transgenic Animal Models to Study Na[superscript +]/H[superscript +] Exchange

2. Transgenic Studies On The NHE1 Isoform Of The Na[superscript +]/H[superscript +] Exchanger 110

2.1 Studies On NHE1 Deficient Mice 110

2.2 Studies Overexpressing The NHE1 Isoform Of The Na[superscript +]/H[superscript +] Exchanger 113

2.3 Transgenic Approaches To Study NHE1 Regulation 113

3. Transgenic Studies On The NHE2 And NHE3 Isoforms Of The Na[superscript +]/H[superscript +] Exchanger 115

3.1 Gastrointestinal Function 115

3.2 Renal Tubular Function 116

4. Pitfalls In Transgenic Studies 117

Chapter 8 pH-Regulatory Mechanisms in the Mammalian Oocyte and Early Embryo

2. Oocyte And Embryo Development 123

3. Expression Of Na[superscript +]/H[superscript +] Exchanger (NHE) And Anion Exchanger (AE) Isoforms In Mammalian PI Embryos 124

4. Activity Of pH[subscript i]-Regulatory Mechanism In PI Embryos 125

4.1 Na[superscript +]/H[superscript +] Exchanger Activity And Recovery From Acidosis In PI Embryos 125

4.2 HCO[subscript 3 superscript -]/Cl[superscript -] Exchanger Activity And Recovery from Alkalosis In PI Embryos 128

5. pH[subscript i] Regulatory Mechanisms During Meiosis And Fertilization 129

5.1 Changes in pH[subscript i] At Fertilization 129

5.2 pH[subscript i] Regulation In The Egg At Fertilization In The Mammal 130

5.3 pH[subscript i] Regulation During Meiosis 130

5.4 Regulation Of HCO[subscript 3 superscript -]/Cl[superscript -] Exchanger Activity During Meiosis 132

Chapter 9 Na[superscript +]/H[superscript +] Exchanger Activation by Myocardial Stretch

2. Mechanism Of Stretch-Induced Increase Of The NHE Activity 138

3. Mechanical Counterpart Of Stretch-Induced Increase Of The NHE Activity 142

Chapter 10 The Paradoxical Role of Na[superscript +]/H[superscript +] Exchanger in the Diabetic Heart

2. Depressed Na[superscript +]/H[superscript +] Exchanger (NHE) Activity In Insulin-Deficient (TYPE I) Diabetes And Associated Increased Resistance Of Diabetic Hearts To Ischemia And Reperfusion Injury 149

3. NHE In Non-Insulin-Dependent (TYPE 2) Diabetes 153

Chapter 11 Role of Na-H Exchanger in Vascular Remodelling in Diabetes

2. Mechanism And Processes Controlling The Activity Of NHE-1 161

3. Cellular Physiology Of The Activation Of NHE 162

4. Ion Transport And Cytoskeleton In The Cellular Function Of NHE1 164

4.1 Vascular Changes In Diabetes 165

4.2 Future Prospects 168

Chapter 12 The Potential Role of the Na[superscript +]/H[superscript +] Exchanger in Ischemia/Reperfusion Injury of the Central Nervous System

2. Na[superscript +]/H[superscript +] Exchange, Stroke And Potential Adverse Consequences 178

2.1 Acidosis And Ischemic Brain Injury 179

2.2 Inhibition Of NHEs During Cerebral Ischemia/Reperfusion 181

Chapter 13 Receptor-Mediated Regulation of the Cardiac Sarcolemmal Na[superscript +]/H[superscript +] Exchanger

2. Regulation Of Cardiac Sarcolemmal NHE Activity By Receptor Activation 193

2.1 Adrenergic Receptors 193

2.2 Angiotensin II Receptors 194

2.3 Endothelin Receptors 195

2.4 Thrombin Receptors 196

2.5 Adenosine Receptors 197

2.6 Muscarinc Receptors 197

2.7 "Orphan" Receptors 197

3. Physiological Importance Of Receptor-Mediated Regulation Of The Sarcolemmal NHE 198

4. Pathophysiological Importance Of Receptor-Mediated Regulation Of The Sarcolemmal NHE 200

4.1 Receptor-Mediated Regulation Of NHE In Myocardial Ischemia And Reperfusion 200

4.2 Receptor-Mediated Regulation Of NHE In Myocardial Hypertrophy 201

Chapter 14 Role of NHE-1 in Cardiac Hypertrophy and Heart Failure

2. Rationale For NHE-1 Involvement In Cardiac Hypertrophy And Heart Failure 212

3. Experimental Evidence For NHE-1 Involvement In Hypertrophy And Heart Failure 213

3.1 Evidence In Cardiac Myocytes And Isolated Tissues 213

3.2 Evidence In Animal Heart Failure Models 215

3.2.1 Postinfarction Heart Failure 215

3.2.2 Right Ventricular Hypertrophy And Heart Failure 216

3.2.3 Genetic Animal Models Of Heart Failure 216

4. Potential Mechanisms For NHE-1 Involvement In Hypertrophy And Heart Failure 216

Chapter 15 Mechanisms Underlying NHE-1 Involvement in Myocardial Ischemic and Reperfusion Injury

2. Cellular Localization Of NHE-1 In The Heart 222

3. Regulation Of NHE-1 Activity In The Cardiac Cell 222

3.2 Activation Of NHE-1 By Cardioactive Paracrine And Autocrine Factors 223

3.3 Role Of Phosphorylation 223

3.4 Phophorylation-Independent

Regulation 224

3.5 Role Of ATP 224

3.6 Activation By G Proteins 225

4. Mechanisms Underlying NHE Involvement In Myocardial Ischemic And Reperfusion Injury 225

4.1 Myocardial Protection By NHE Inhibitors 228

4.2 Does NHE-1 Mediated Injury Occur During Ischemia Or Reperfusion, Or Both? 228

5. Potent Antiarrhythmic Effect Of NHE-1 Inhibition 230

6. Other Potential Mechanims Mediating Cardioprotective Effects Of NHE-1 Inhibitors 232

Chapter 16 Chemistry of NHE Inhibitors

1.1 The Importance Of The Guanidine Moiety 239

2. Chemical Classes Of NHE Inhibitors 242

2.1 Aroylguanidines 242

2.2 Heteroaroylguanidines 243

2.2.1 6-Membered Heteroaroylguanidines 243

2.2.2 5-Membered Heteroaroylguanidines 244

2.3 Spacer-Stretched Aroylguandines 246

2.4 Non-Acyl Guanidines 248

2.5 Non-Guanidine NHE Inhibitors 249

Chapter 17 Development of NHE Inhibitors for Cardiovascular Therapeutics

2. Clinical Trials Performed With NHE-1 Inhibitors In Patients Exposed To Myocardial Ischemia/Reperfusion 256

2.1 The GUARDIAN Trial 257

2.2 The ESCAMI Trial 257

2.3 The EXPEDITION Trial 258

3. Apparent Contradiction Between Preclinical Data Of NHE-1 Inhibitors And The Outcome Of Clinical Trials 258

4. Preclinical Evidence For A Central Role Of NHE-1 In Post MI Remodeling And Heart Failure 261

Chapter 18 Cardiac Protection by NHE Inhibitors

2. NHE-1 Inhibition And Cardioprotection 266

2.1 Mechanisms Responsible For Cardioprotection 266

2.2 NHE-1 Inhibition And Infarct Size Reduction 268

2.3 Comparative Effects of NHE-1 Inhibition And Ischemic Preconditioning To Reduce Infarct Size 270

2.4 Apoptosis And NHE-1 Inhibition 273

2.4 Antifibrillatory And antiarrhythmic Effects Of NHE-1 Inhibitors 274

3. Clinical Trials With NHE-1 Inhibitors: Infarct Size Reduction 274

Chapter 19 NHE-1 Inhibitors: Potential Application in Cardiac Surgery

2. Myocardial Dysfunction After Cardiac Surgery 280

3. Cardioprotective Effects Of NHE-1 Inhibition 281

4. Myocardial Protection For Transplantation 283

5. Potential For NHE-1 Activation During Cardiac Surgery 285

6. Clinical Studies Of NHE-1 Inhibition In Cardiac Surgery 287

Chapter 20 NHE-1 Inhibition: A Potential New Treatment for Resuscitation from Cardiac Arrest

2. Potential Role Of NHE-1 During Cardiac Arrest 292

3. Myocardial Effects Of Ventricular Fibrillation 294

4. NHE-1 Inhibitors 295

5. Myocardial Abnormalities During VF And Effects Of NHE-1 Inhibition 297

5.1 Ischemic Contracture And Closed-Chest Resuscitation 297

5.2 Myocardial Perfusion And Coronary Vascular Resistance 298

5.3 Timing For Electrical Defibrillation 299

5.4 Ventricular Arrhythmias After Return Of Spontaneous Circulation 300

5.5 Post-Resuscitation Myocardial Dysfunction 301

6. Clinical Implications 302.

Notes:

Includes bibliographical references and index.

ISBN:

1402074743

OCLC:

52085969