Extracellular and Intracellular Signaling Edited by James D. Adams, Jr. School of Pharmacy, University of Southern California. Los Angeles. CA, USA Keith K. Parker Department of Biomedical and Pharmaceutical Sciences Skaggs School of Pharmacy and Allied Health Sciences, University of Montana, Missoula, MT, USA Publishing
Contents Chapter 1 Extracellular and Intracellular Signaling - a New Approach to Diseases and Treatments 1 James David Adams, Jr., Eric J. Lien and Keith Parker Introduction 1 1.1.1 Linear Model of Drug Receptor Interactions 1 1.1.2 Matrix Model of Drug Receptor Interactions 2 1.2 Experimental Approaches to Disease Treatment 3 Adipokines and Disease Causation 4 1.4 Questions in Disease Treatment Toxic Lifestyles and 7 9 Chapter 2 Autocrine Effects in White Adipose Tissue and Pancreatic Islets: Emergent Roles in the Regulation of and Pancreatic Function 10 Mary C. Sugden and Mark J. Holness 2.1 Introduction 10 2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion 2.3 Feedback between FA and the Adipocyte 14 2.4 Autocrine Effects of Leptin and Adiponectin in Adipocytes 2.5 Potential Effects of Deficiency on Autocrine Signaling in Adipose Tissue RSC Drug Discovery Series No. 10 Extracellular and Signaling Edited by James D. Adams. Jr. and Keith K. Parker Royal Society of Chemistry Published by the Royal Society of www.rsc.org vii
viii Contents 2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue 19 2.7 Autocrine Effects on Adipose Tissue Could Modulate the Operation of the Adipocyte Circadian Clock 20 2.8 Cell Heterogeneity in the Pancreatic Islet 21 2.9 Autocrine Effects of Insulin on the Pancreatic p Cell 22 2.10 Is Early Life Programming of Insulin Resistance by Altered Insulin Signaling Accompanied by an Abnormal Autocrine Effect of Insulin on the Pancreatic Cell? 25 Effects of FA on the Pancreatic cell 26 Effects of Leptin and Adiponectin on the Pancreatic Cell 27 Effects of on the p Cell 29 2.14 Is Programmed Obesity Associated with Inflammation? 29 Other Adipose-derived Factors that Could Contribute to the Adipoinsular Axis 30 2.16 Concluding Remarks 32 Acknowledgements 32 32 Chapter 3 One Receptor for Multiple Pathways: Focus on Leptin Signaling 44 Rodolfo Javier Conde, Morena Seotece and Oreste 3.1 Leptin 44 3.2 Leptin Receptors 45 3.3 Leptin Receptor Signaling 45 3.3.1 The JAK2-STATs Routes 45 3.3.2 ERK1/2 48 3.3.3 PI3K/AKT 49 3.3.4 AMPK 49 3.3.5 SOCS3 50 3.4 Leptin Receptor Interactions 50 3.4.1 Apolipoprotein D 51 3.4.2 Sorting Nexin Molecules 51 3.4.3 Diacylglycerol Kinase Zeta 51 3.4.4 Apolipoprotein J 52
ix Chapter 4 Cell Signaling Mechanisms Underlying the Cardiac Actions of Adipokines 57 Morris Karmazyn and Introduction 57 4.2 Leptin: A Brief 58 4.3 Expression of Leptin Receptors in Cardiovascular Tissues 58 4.4 Effect of Leptin on Function 59 4.5 Hypertrophic Effects of Leptin 59 4.6 Post Receptor Leptin Signaling 61 4.6.1 Pathway Activation 61 4.6.2 Mitogen Activated Protein Kinase Stimulation 62 4.6.3 Pivotal Role for the RhoA ROCK System in Mediating the Hypertrophic Effects of Leptin 63 4.7 Adiponectin 63 4.7.1 Adiponectin and Cardiovascular Disease 64 4.7.2 Adiponectin and Experimental Cardiac Hypertrophy 64 4.7.3 Cell Signaling Mechanisms Underlying Cardioprotective and Effects of Adiponectin 65 4.8 Resistin 66 4.8.1 Cardiac Actions of Resistin 67 4.9 Apclin 67 4.9.1 Apclin and Heart Disease 68 4.10 Visfatin 68 Other Novel Adipokines 69 4.12 Summary. Conclusions and Future Directions 70 Acknowledgements 70 70 Chapter 5 Regulation of Muscle Proteostasis via Extramuscular Signals 77 Philip J. ton and Nathaniel Szewczyk 5.1 Basic Protein Synthesis 77 5.2 The Effects of Extramuscular Signals on Global Proteostasis in Muscle 79 5.2.1 Hormones 79 5.2.2 Local Factors 82 5.3 Regulation of Muscle Proteostasis in Humans 88 5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man 89 5.3.2 Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis 92
x Contents 5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans 95 5.4.1 Effects of Aging on Muscle Proteostasis 96 5.4.2 Disuse Atrophy 97 5.4.3 Sepsis 99 5.4.4 Burns 100 5.4.5 Cancer Cachexia 101 102 Chapter 6 Contact Normalization: Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets 105 Jhon Alberto Candacy George, Harini Krishnan, Xiaoxuan Wu and Gary S. Goldberg 6.1 Introduction 105 6.2 Contact Normalization 106 6.3 Cadherins 106 6.4 Gap Junctions 107 6.5 Contact Normalization and Tumor Suppressors 108 6.6 Contact Normalization and Tumor Promoters 109 6.7 Conclusions Chapter 7 Involvement of Adipokines in Migraine Headache Keith K. Parker 7.1 Introduction 7.2 Background on Migraine Headache 117 7.3 Migraine and Neuropathic Pain 7.4 Role of Astrocytes in Pain 121 7.5 Adipokines and Related Extracellular Signalling 122 7.6 The Future of Signaling Research to Migraine 125 Acknowledgements 125 125 Chapter 8 Adipokines and Alzheimer's Disease 130 Maria Angela Sortino, Sara and 8.1 Alzheimer's Disease 130 and Tau 131 8.1.2 Target for AD Therapy 133 8.2 AD and Metabolic Dysfunction 134 8.2.1 Impaired Glucose Metabolism 134 8.2.2 Lipid Disorders 135 8.2.3 Obesity
Contents 8.3 Adipokines 136 8.3.1 Leptin 137 8.3.2 Adiponectin 139 8.3.3 Resistin 139 8.3.4 Visfatin 140 8.3.5 Plasminogen Activator 140 8.3.6 8.3.7 Transforming Growth Factor-pi 141 8.4 Conclusions 142 xi Chapter 9 Astrocyte Signaling in Neurological Disorders 149 A. R. Jayakumar and M. D. Norenberg 9.1 Introduction 149 9.1.1 Structure and Function of Astrocytes 149 9.1.2 Responses of Astrocytes to Injury 151 9.2 Intracellular Signaling System in Reactive Astrocytes 155 9.2.1 Oxidative/Nitrosative Stress (ONS) 155 9.2.2 Protein Kinase C (PKC) 156 9.2.3 (PI3K) 156 9.2.4 Mitogen-activated Protein Kinases (MAPKs) 9.2.5 Signal Transducer and Activator of Transcription 3 (STAT3) 157 9.2.6 Nuclear Factor Kappa B (NF-KB) 158 9.3 Signaling in Astrocyte Swelling 158 (ONS) 159 9.3.2 Cytokines 159 Signaling Kinases 160 9.3.3 Protein Kinase C (PKC) 9.3.4 Phosphatidylinositol 3-Kinase (PI3K) 160 9.3.5 Protein Kinase G (PKG) 160 9.3.6 Mitogen-activated Protein Kinases (MAPKs) 161 Transcription Factors 9.3.7 Signal Transducer and Activator 3 (STAT3) 161 9.3.8 Nuclear Factor Kappa B (NF-KB) 161 9.3.9 p53 162 Swelling Effectors Exchangers 162 9.3.11 (AQP-4) 9.4 Conclusions and Acknowledgements 165
xii Contents Chapter 10 DNA, Nuclear Cell Signaling and Neurodegeneration 175 James D. Adams, Jr., Ph.D. 10.1 Adipokines, Toxic Lipids and the Aging Brain 175 10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids 176 10.1.2 Ceramide Toxicity in the Brain 10.1.3 Endocannabinoids, Ceramide and Amyloidp 177 10.2 The Blood-Brain Barrier as a Target for Neurodegenerative Conditions 178 10.2.1 Visfatin and the Blood-Brain Barrier 178 10.3 Oxygen Radicals, Hydrogen Peroxide and Cell Death 10.4 Gene Transcription and DNA Damage 183 10.5 Conclusions 184 Chapter G Protein-Coupled Receptors: Conformational "Gatekeepers" of Transmembrane Signal Transduction and Diversification 188 Ravinder and William A. Goddard III, FRSC Introduction 188 11.2 Cellular Signaling 190 Types of Signaling 190 Membrane Proteins in Signaling 11.3 G Protein-Coupled Receptors 192 Structure of GPCRs 193 GPCR Activation: Conformation Functional Selectivity 203 Functional Control of GPCRs by Ligands Challenges in GPCR Targeted Drug Design 221 Summary and Looking Ahead 223 Acknowledgements 224 225 Chapter 12 as Modulators of Signaling in Inflammation 230 Lori 12.1 Introduction 230 12.2 Overview of the Inflammatory Cascade 231 12.3 of NF-KB 232 12.4 PPARy and LXRs Regulate NF-KB 233 Natural Products and Inhibitors of NF-KB 235 Anthocyanins 235 12.5.2 Gallates 236
Contents 12.5.3 Quercetin 12.5.4 Isollavones 237 12.5.6 Gingerol 239 12.5.7 Curcumin 239 12.5.8 240 12.6 Agonists of PPARy that Reciprocally Inhibit NF-KB 12.6.1 Phytanic Acid 12.6.2 Dehydroabietic Acid 241 12.6.3 Geraniol 242 12.7 Agonists of LXR that Reciprocally Inhibit NF-KB 242 12.7.1 242 12.7.2 243 12.7.3 Ergosterol 243 12.8 Conclusion 243 244 Chapter 13 Intracellular Signaling Pathways in Parkinson's Disease 247 Monica Sanchez and Fernando 13.1 Introduction 247 13.2 Selective Dopaminergic Neuronal Death 13.3 Signaling Pathways Involved in Selective Dopaminergic Neuronal Death 254 Initiators and Signaling 254 Signal Transducers. Intracellular Messengers and Upstream Elements 261 Signaling Cascades 263 13.3.4 Potentially Involved Intracellular Signaling Components 266 13.3.5 Effector Pathways and Final Effects 267 13.4 Conclusions 270 271 Subject Index 283