Extracellular and Intracellular Signaling

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1 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

2 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 Linear Model of Drug Receptor Interactions Matrix Model of Drug Receptor Interactions Experimental Approaches to Disease Treatment 3 Adipokines and Disease Causation 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 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion 2.3 Feedback between FA and the Adipocyte 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 vii

3 viii Contents 2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue Autocrine Effects on Adipose Tissue Could Modulate the Operation of the Adipocyte Circadian Clock Cell Heterogeneity in the Pancreatic Islet Autocrine Effects of Insulin on the Pancreatic p Cell 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 Is Programmed Obesity Associated with Inflammation? 29 Other Adipose-derived Factors that Could Contribute to the Adipoinsular Axis Concluding Remarks 32 Acknowledgements Chapter 3 One Receptor for Multiple Pathways: Focus on Leptin Signaling 44 Rodolfo Javier Conde, Morena Seotece and Oreste 3.1 Leptin Leptin Receptors Leptin Receptor Signaling The JAK2-STATs Routes ERK1/ PI3K/AKT AMPK SOCS Leptin Receptor Interactions Apolipoprotein D Sorting Nexin Molecules Diacylglycerol Kinase Zeta Apolipoprotein J 52

4 ix Chapter 4 Cell Signaling Mechanisms Underlying the Cardiac Actions of Adipokines 57 Morris Karmazyn and Introduction Leptin: A Brief Expression of Leptin Receptors in Cardiovascular Tissues Effect of Leptin on Function Hypertrophic Effects of Leptin Post Receptor Leptin Signaling Pathway Activation Mitogen Activated Protein Kinase Stimulation Pivotal Role for the RhoA ROCK System in Mediating the Hypertrophic Effects of Leptin Adiponectin Adiponectin and Cardiovascular Disease Adiponectin and Experimental Cardiac Hypertrophy Cell Signaling Mechanisms Underlying Cardioprotective and Effects of Adiponectin Resistin Cardiac Actions of Resistin Apclin Apclin and Heart Disease Visfatin 68 Other Novel Adipokines Summary. Conclusions and Future Directions 70 Acknowledgements Chapter 5 Regulation of Muscle Proteostasis via Extramuscular Signals 77 Philip J. ton and Nathaniel Szewczyk 5.1 Basic Protein Synthesis The Effects of Extramuscular Signals on Global Proteostasis in Muscle Hormones Local Factors Regulation of Muscle Proteostasis in Humans Nutrients as Regulators of Muscle Proteostasis in Man Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis 92

5 x Contents 5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans Effects of Aging on Muscle Proteostasis Disuse Atrophy Sepsis Burns Cancer Cachexia 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 Contact Normalization Cadherins Gap Junctions Contact Normalization and Tumor Suppressors Contact Normalization and Tumor Promoters Conclusions Chapter 7 Involvement of Adipokines in Migraine Headache Keith K. Parker 7.1 Introduction 7.2 Background on Migraine Headache Migraine and Neuropathic Pain 7.4 Role of Astrocytes in Pain Adipokines and Related Extracellular Signalling The Future of Signaling Research to Migraine 125 Acknowledgements Chapter 8 Adipokines and Alzheimer's Disease 130 Maria Angela Sortino, Sara and 8.1 Alzheimer's Disease 130 and Tau Target for AD Therapy AD and Metabolic Dysfunction Impaired Glucose Metabolism Lipid Disorders Obesity

6 Contents 8.3 Adipokines Leptin Adiponectin Resistin Visfatin Plasminogen Activator Transforming Growth Factor-pi Conclusions 142 xi Chapter 9 Astrocyte Signaling in Neurological Disorders 149 A. R. Jayakumar and M. D. Norenberg 9.1 Introduction Structure and Function of Astrocytes Responses of Astrocytes to Injury Intracellular Signaling System in Reactive Astrocytes Oxidative/Nitrosative Stress (ONS) Protein Kinase C (PKC) (PI3K) Mitogen-activated Protein Kinases (MAPKs) Signal Transducer and Activator of Transcription 3 (STAT3) Nuclear Factor Kappa B (NF-KB) Signaling in Astrocyte Swelling 158 (ONS) Cytokines 159 Signaling Kinases Protein Kinase C (PKC) Phosphatidylinositol 3-Kinase (PI3K) Protein Kinase G (PKG) Mitogen-activated Protein Kinases (MAPKs) 161 Transcription Factors Signal Transducer and Activator 3 (STAT3) Nuclear Factor Kappa B (NF-KB) p Swelling Effectors Exchangers (AQP-4) 9.4 Conclusions and Acknowledgements 165

7 xii Contents Chapter 10 DNA, Nuclear Cell Signaling and Neurodegeneration 175 James D. Adams, Jr., Ph.D Adipokines, Toxic Lipids and the Aging Brain Toxic Lifestyles, Adipokines and Toxic Lipids Ceramide Toxicity in the Brain Endocannabinoids, Ceramide and Amyloidp The Blood-Brain Barrier as a Target for Neurodegenerative Conditions Visfatin and the Blood-Brain Barrier Oxygen Radicals, Hydrogen Peroxide and Cell Death 10.4 Gene Transcription and DNA Damage Conclusions 184 Chapter G Protein-Coupled Receptors: Conformational "Gatekeepers" of Transmembrane Signal Transduction and Diversification 188 Ravinder and William A. Goddard III, FRSC Introduction 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 Chapter 12 as Modulators of Signaling in Inflammation 230 Lori 12.1 Introduction Overview of the Inflammatory Cascade of NF-KB PPARy and LXRs Regulate NF-KB 233 Natural Products and Inhibitors of NF-KB 235 Anthocyanins Gallates 236

8 Contents Quercetin Isollavones Gingerol Curcumin Agonists of PPARy that Reciprocally Inhibit NF-KB Phytanic Acid Dehydroabietic Acid Geraniol Agonists of LXR that Reciprocally Inhibit NF-KB Ergosterol Conclusion Chapter 13 Intracellular Signaling Pathways in Parkinson's Disease 247 Monica Sanchez and Fernando 13.1 Introduction 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 Potentially Involved Intracellular Signaling Components Effector Pathways and Final Effects Conclusions Subject Index 283

Molecular Cell Biology - Problem Drill 19: Cell Signaling Pathways and Gene Expression

Molecular Cell Biology - Problem Drill 19: Cell Signaling Pathways and Gene Expression Question No. 1 of 10 1. Which statement about cell signaling is correct? Question #1 (A) Cell signaling involves receiving