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| עמודים / Pages | 264 |
|---|---|
| פורמט | Paperback / softback |
| ISBN10 | 3527337261 |
| יצא לאור ב | Weinheim |
| תאריך יציאה לאור | 16 במרץ 2016 |
| תוכן עניינים | Acknowledgment XIII Part I Introduction 1 1 Introduction 3 1.1 Receptors and Signaling 3 1.1.1 General Aspects of Signaling 3 1.1.2 Verbal and Physiological Signals 3 1.1.3 Criteria for Recognizing Transmitters and Receptors 4 1.1.4 Agonists 4 1.1.5 Receptors 4 1.1.6 Receptor Enzyme Similarities 4 1.2 Types of Receptors and Hormones 5 1.2.1 Receptor Superfamilies 5 1.3 Receptors Are the Chemical Expression of Reality 6 2 The Origins of Chemical Thinking 9 2.1 Overview of Early Pharmacological History 9 2.1.1 The Development of a Chemical Hypothesis 9 2.1.2 Chemical Structure and Drug Action 10 2.1.3 The Site of Drug Action 10 2.2 Modern Pharmacology 10 2.2.1 Langley and Ehrlich: the Origins of the Receptor Concept 10 2.2.2 Maturation of the Receptor Concept 13 2.3 Phylogenetics of Signaling 13 2.3.1 The First Communicators 13 Part II Fundamentals 15 3 Membranes and Proteins 17 3.1 Membranes 17 3.1.1 The Cytoplasmic Membrane the Importance of Cell Membranes 17 3.1.2 History of Membrane Models 17 3.1.2.1 The Roles of Proteins in Membranes 18 3.1.2.2 Challenges to the Danielli Davson Model 19 3.1.2.3 A New View of Membrane Proteins 19 3.1.2.4 The Modern Concept of Membranes the Fluid Mosaic Model 19 3.1.3 Membrane Components 19 3.1.3.1 Membrane Lipids 19 3.1.3.2 Asymmetry and Heterogeneity in Membrane Lipids 20 3.1.3.3 Membrane Construction and Insertion of Proteins 20 3.2 The Nature and Function of Proteins 21 3.2.1 Linear andThree-Dimensional Structures 22 3.2.2 Primary Structure 22 3.2.3 Secondary Structure 23 3.2.4 Tertiary Structure 24 3.2.5 Protein Domains 25 3.2.6 Proteomics 25 4 Hormones as First Messengers 27 4.1 Hormones and Cellular Communication 27 4.1.1 Discovery of Hormones 27 4.2 Types of Hormones 27 4.2.1 Pheromones for Signaling between Individuals 28 4.2.2 Archaea and Bacteria 28 4.2.3 Eukaryotes 29 4.2.3.1 Chromalveolates 29 4.2.3.2 Unikonts Amoebozoa, Fungi, Animals 29 4.2.3.3 Invertebrate Pheromones 31 4.2.3.4 Vertebrate Pheromones 31 4.3 Vertebrate Hormones and Transmitters 31 4.3.1 Peptide and Non-Peptide Agonists 31 4.3.1.1 Peptides 31 4.3.1.2 Non-peptides 31 4.3.2 Peptide Hormones of the G-Protein-Coupled Receptors 32 4.3.2.1 Hypothalamic-Pituitary Axis 32 4.3.2.2 The Anterior Pituitary Trophic Hormones 34 4.3.3 Other Neural Peptides 35 4.3.3.1 Opioids 35 4.3.3.2 Non-Opioid Transmitter Peptides 36 4.3.4 Peptides from Non-Neural Sources 36 4.3.4.1 Digestive Tract Hormones 36 4.3.4.2 Hormones from Vascular Tissue 38 4.3.4.3 Hormones from the Blood 38 4.3.4.4 Peptide Hormones from Reproductive Tissues 39 4.3.4.5 Hormones from Other Tissues 39 4.3.5 Non-Peptides Acting on G-Protein-Coupled Receptors 39 4.3.5.1 Transmitters Derived from Amino Acids 39 4.3.5.2 Transmitters Derived from Nucleotides 40 4.3.5.3 Transmitters Derived from Membrane Lipids Prostaglandins and Cannabinoids 41 4.3.6 Transmitters of the Ion Channels 41 4.3.7 Hormones of the Receptor Kinases Growth Factor Receptors 43 4.3.7.1 Insulin 43 4.3.7.2 Insulin-Like Growth Factors 43 4.3.7.3 Natriuretic Peptides 43 4.3.7.4 Peptide Signal Molecules Important in Embryogenesis 43 4.3.7.5 Pituitary Gland Hormones Somatotropin and Prolactin 43 4.3.8 Hormones of the Nuclear Receptors 44 4.3.8.1 Steroids 44 4.3.8.2 Non-Steroid Nuclear Hormones 46 4.4 Analgesics and Venoms as Receptor Ligands 46 5 Receptor Theory 47 5.1 The Materialization of Receptors 47 5.2 ReceptorMechanisms 47 5.2.1 Binding of Agonist to Receptor 48 5.2.1.1 Bonds 48 5.3 Binding Theory 49 5.3.1 Early Approaches to Understanding Receptor Action 49 5.3.1.1 The Occupancy Model 49 5.3.1.2 Processes That Follow Receptor Activation 52 5.3.1.3 Efficacy and Spare Receptors 52 5.3.2 Modern Approaches to Receptor Theory 52 5.3.2.1 The Two-State Model 52 5.3.2.2 The Ternary Complex Model 53 5.3.2.3 Protean Agonism 54 5.3.2.4 Cubic Ternary Complex (CTC) Model 55 5.3.3 Summary of Model States 55 5.4 Visualizing Receptor Structure and Function 55 5.4.1 Determination of Receptor Kd 55 5.4.1.1 Schild Analysis 56 5.4.2 Visualizing Ligand Binding 57 5.4.2.1 Receptor Preparation 58 5.4.2.2 Equilibrium Binding Studies 58 5.4.2.3 Competition Studies 58 5.4.3 X-ray Crystallography of Native and Agonist-Bound Receptors 59 5.4.4 Probe Tagging (Fluorescent and Photoaffinity) 60 5.5 Proteomics Approaches to Receptor Efficacy 60 5.6 Physical Factors Affecting Receptor Binding 61 5.6.1 Temperature 61 5.6.2 Relation of Agonist Affinity and Efficacy to Distance Traveled Following Release 61 Part III Receptor Types and Function 63 6 Transduction I: Ion Channels and Transporters 65 6.1 Introduction 65 6.1.1 Family Relationships 65 6.2 Small Molecule Channels 66 6.2.1 Osmotic and Stretch Detectors 66 6.2.2 Voltage-Gated Cation Channels 66 6.2.2.1 History of Studies on Voltage-Gated Channels 66 6.2.2.2 Structure and Physiology of Ion Channels 68 6.2.3 Potassium Channels 68 6.2.4 Sodium Channels 70 6.2.4.1 Bacterial Na+ Channels 70 6.2.4.2 Vertebrate Na+ Channels 70 6.2.5 Calcium Channels 71 6.2.6 Non-Voltage-Gated Cation Channels Transient Receptor Potential (TRP) Channels 72 6.3 Transporters 73 6.3.1 Pumps and Facilitated Diffusion 73 6.3.1.1 The SLC Proteins 73 6.3.1.2 The Pumps 74 6.3.2 The Chloride Channel 76 6.4 Major Intrinsic Proteins 76 6.4.1 Water Channels 76 6.4.2 Glycerol Transporters 77 6.5 Ligand-Gated Ion Channels 77 6.5.1 Four-TM Domains the Cys-Loop Receptors 77 6.5.1.1 The Four-TM Channels for Cations 78 6.5.1.2 The Four-TM Channels for Anions 80 6.5.2 Three-TM Domains Ionotropic Glutamate Receptors 82 6.5.2.1 Glutamate-Gated Channels 82 6.5.2.2 N-Methyl-D-aspartate (NMDA) Receptor 82 6.5.2.3 Non-NMDA Receptors 82 6.5.3 Two-TM Domains ATP-Gated Receptors (P2X) 82 7 Transduction II: G-Protein-Coupled Receptors 85 7.1 Introduction 85 7.1.1 Receptor Function 86 7.1.2 Sensory Transduction 87 7.1.2.1 Chemoreception in Non-Mammals 87 7.1.2.2 Chemoreception in Mammals 87 7.2 Families of G-Protein-Coupled Receptors 89 7.3 Transduction Mechanisms 89 7.3.1 Discovery of Receptor Control of Metabolism Cyclic AMP and G Proteins 89 7.3.1.1 Components of the Process of Metabolic Activation 89 7.3.1.2 Discovery of Cyclic AMP 90 7.3.1.3 Discovery of G Proteins 90 7.3.2 Actions of G Proteins 91 7.3.2.1 G-Alpha Proteins 92 7.3.2.2 Roles of the Beta and Gamma Subunits 95 7.3.3 Proteins That Enhance (GEF) or Inhibit (GAP) GTP Binding 96 7.3.3.1 GEF Protein 96 7.3.3.2 GAP Protein 96 7.3.4 Signal Amplification 97 7.3.5 Signal Cessation Several Processes Decrease Receptor Activity 97 7.3.6 Interactions between Receptors and G Proteins 97 7.3.7 Summary of Actions of GPCRs: Agonists, Receptors, G Proteins, and Signaling Cascades 98 7.4 The Major Families of G Protein-Coupled Receptors 99 7.4.1 Family A Rhodopsin-Like 99 7.4.1.1 The Subfamily 99 7.4.1.2 The Subfamily 102 7.4.1.3 The Subfamily 102 7.4.1.4 The Subfamily 104 7.4.2 Family B Secretin-Like 104 7.4.3 Family C Metabotropic Glutamate and Sweet/Umami Taste Receptors 104 7.4.3.1 Taste 1 Receptors (T1Rs) 105 7.4.3.2 Calcium-Sensing Receptors 106 7.4.4 Family D Adhesion Receptors 106 7.4.5 Family F Frizzled-Smoothened Receptors 106 7.4.6 Family E Cyclic AMP Receptors 106 7.4.7 Other G-Protein-Coupled Receptor Types in Eukaryotes 106 7.4.7.1 Yeast Mating Pheromone Receptors 106 7.4.7.2 Insect Taste Receptors 106 7.4.7.3 Nematode Chemoreceptors 106 8 Transduction III: Receptor Kinases and Immunoglobulins 107 8.1 Protein Kinases 107 8.2 Receptors for Cell Division and Metabolism 108 8.2.1 Overview of Family Members 108 8.2.2 Overall Functions of RTK 108 8.2.2.1 Extracellular Domains 108 8.2.2.2 Intracellular Domains 109 8.2.3 Receptor Tyrosine Kinase Subfamilies 110 8.2.3.1 EGF Receptor Subfamily 111 8.2.3.2 Insulin Receptor Subfamily 111 8.2.3.3 FGF and PDGF Receptor Subfamilies 111 8.2.3.4 NGF Receptor Subfamily 111 8.3 Receptor Serine/Threonine Kinases 112 8.3.1 Transforming Growth Factor-Beta (TGF- ) Receptor 112 8.4 The Guanylyl Cyclase Receptor Subfamily Natriuretic Peptide Receptors 112 8.5 Non-Kinase Molecules LDL Receptors 113 8.5.1 Cholesterol Transport 113 8.5.2 The Low-Density Lipoprotein (LDL) Receptor 114 8.5.2.1 Clathrin-Coated Pits 114 8.6 Cell Cell Contact Signaling 115 8.6.1 Notch Delta Signaling 115 8.7 Immune System Receptors, Antibodies, and Cytokines 115 8.7.1 The Innate Immune Responses 115 8.7.2 The Cells and Molecules of the Adaptive Immune System 116 8.7.3 T-Cell Receptors and Immunoglobulins 116 8.7.4 Cell-Surface Molecules 117 8.7.4.1 The MHC Proteins 117 8.7.4.2 Receptors of the B and T Cells 118 9 Transduction IV: Nuclear Receptors 121 9.1 Introduction 121 9.2 Genomic Actions of Nuclear Receptors 122 9.2.1 Families of Nuclear Receptors 122 9.2.2 Transcription Control 122 9.2.3 Constitutively Active Nuclear Receptors 122 9.2.4 Liganded Receptors 122 9.2.5 History of Steroid Receptor Studies 123 9.2.6 Receptor Structure 123 9.2.7 The Ligand-Binding Module 124 9.2.8 The DNA-BindingModule 125 9.2.9 Specific Nuclear Actions 125 9.2.9.1 Family 1 Thyroid Hormone and Vitamins A and D Receptors 125 9.2.9.2 Family 2 Fatty Acid (HNF4) and Retinoic X Receptors (RXR) 127 9.2.9.3 Family 3 Steroid Receptors for Estrogens, Androgens, Progestogens, Mineralocorticoids, and Glucocorticoids 128 9.3 Actions of Receptor Antagonists 129 9.4 Non-Traditional Actions of Steroid-Like Hormones andTheir Receptors 130 9.4.1 Cell-Membrane Progesterone Receptors 131 9.4.2 Cell-Membrane Mineralocorticoid and Glucocorticoid Receptors 131 9.4.3 Cell-MembraneThyroid Hormone and Vitamin A/D Receptors 131 9.4.4 Ligand-Independent Activation of Transcription 131 Part IV Applications 133 10 Signaling Complexity 135 10.1 Introduction 135 10.2 Experimental Determination of Signaling Cascades 135 10.2.1 Glycolysis 135 10.2.2 MAPK: a Phosphorylation Cascade 136 10.3 Transduction across theMembrane 138 10.3.1 Ion Channels 138 10.3.2 G-Protein-Coupled Receptors 138 10.3.2.1 Other G-Protein-Like Transducers Ras 139 10.3.2.2 Other G-Protein-Like Transducers Ran 139 10.3.3 Cell Aggregation and Development 140 10.3.3.1 Coaggregation in Bacteria 140 10.3.3.2 Aggregation in Eukaryotes 140 10.3.3.3 The Molecules of Cell Adhesion 141 10.4 Complexity in Cross Talk Roles of PIP3, Akt, and PDK1 141 10.4.1 Signaling Cascades Using PIP3 142 10.4.2 Integrins 144 10.4.3 Receptor Tyrosine Kinases 144 10.4.4 Cytokine Receptors and the JAK/STAT Proteins 144 10.4.5 Combined Cellular Signaling GPCR and RTK Actions 144 10.5 Role in Cancer 144 10.5.1 Constitutive versus Inducible Activation 144 10.5.2 Cancer Pathways 146 10.6 Signaling Mediated by Gas Molecules 146 10.6.1 Carbon Monoxide 147 10.6.2 Nitric Oxide 147 10.6.3 Hydrogen Sulfide 148 11 Cellular Interactions in Development 149 11.1 Introduction 149 11.2 The Origins of Multicellularity 150 11.2.1 Multicellular Lineages in Prokaryotes 150 11.2.2 Multicellular Lineages in Eukaryotes 150 11.2.2.1 Chromalveolates Generally Unicellular but with One Multicellular Clade 151 11.2.2.2 Archaeplastida Algae and Plants 151 11.2.2.3 Amoebozoans, Fungi, Choanoflagellates, and Animals 151 11.3 The Origin of Symmetry and Axes 152 11.3.1 The Multicellular Body Plan 152 11.3.2 The Porifera Asymmetric with a Single Cell Layer 152 11.3.3 Cnidaria Radial Symmetry, Two Cell Layers, Tissues 153 11.3.4 Mesoderm 154 11.4 Fertilization and Organization of the Multicellular Body Plan 154 11.4.1 Sperm Egg Recognition 154 11.4.1.1 Sea Urchin Fertilization 154 11.4.1.2 Mammalian Fertilization 157 11.5 Differentiation of Triploblastic Embryos Organogenesis 158 11.5.1 Introduction 158 11.5.2 The Origin of Triploblastic Animals 158 11.5.3 Development in Protostomes 159 11.5.3.1 Segmentation and Organ Formation in Drosophila 159 11.5.3.2 Cellular Interactions in Later Drosophila Development 161 11.5.4 Development in Deuterostomes 162 11.5.4.1 Early Frog Development 162 11.5.4.2 Nerve Growth 164 11.6 Programmed Cell Death (Apoptosis) 165 11.6.1 Apoptosis During Development 166 11.6.2 Apoptosis During Adult Life 166 12 Receptor Mechanisms in Disease Processes 169 12.1 Genetic Basis for Receptor Function 169 12.1.1 Genotype and Phenotype 169 12.1.2 Classical Dominance Mechanisms 169 12.1.3 Other Levels of Gene Expression 170 12.1.4 Pre-receptor Mutations 170 12.1.5 Receptor Mutations 171 12.1.6 Post-receptor Mutations 171 12.2 Receptor Pathologies 171 12.2.1 Ion Channel Superfamily 171 12.2.1.1 Calcium Channels 172 12.2.1.2 Transient Receptor Protein (TRP) Channels 172 12.2.1.3 Voltage-Gated Na+ Channels 172 12.2.1.4 Ligand-Gated Na+ Channels 172 12.2.1.5 Chloride Transporter Cystic Fibrosis 172 12.2.2 G-Protein-Coupled Receptor Superfamily 172 12.2.2.1 Cholera 172 12.2.2.2 Thyroid Diseases 173 12.2.2.3 Cardiovascular Disease 173 12.2.2.4 Obesity 174 12.2.2.5 Depression 175 12.2.2.6 Schizophrenia 175 12.2.3 Immunoglobulin Superfamily 176 12.2.3.1 Diabetes Mellitus 176 12.2.3.2 Atherosclerosis 176 12.2.4 Nuclear Receptor Superfamily Steroid Receptors 176 12.2.4.1 Alterations in Transcription 176 12.2.4.2 Additional Effects 177 12.3 Signaling Mutations Leading to Cancer 177 12.3.1 Pathogenesis of Cancer 177 12.3.2 Cancer as a Disease of Signaling Molecules 178 12.3.2.1 Oncogenes that Encode Mutated Transmitters 178 12.3.2.2 Oncogenes that Encode Mutated RTKs 178 12.3.2.3 Oncogenes that Encode Mutated G Proteins 179 12.3.2.4 Oncogenes that Encode Mutated Transcription Factors Steroid Receptors 180 13 Receptors and the Mind 181 13.1 Origins of Behavior 181 13.1.1 Bacterial Short-Term Memory 181 13.1.2 AnimalsWithout True Neural Organization:The Porifera 182 13.1.3 Animals with Neural Networks: The Cnidaria 182 13.1.4 Bilaterally Symmetrical Animals: The Acoela 183 13.2 Nervous Systems 183 13.2.1 Organization 183 13.2.2 Neurons 183 13.2.2.1 Cell Structure 183 13.2.2.2 Mechanisms 184 13.2.3 Transmitters 184 13.2.3.1 Synthesis and Release of Brain Transmitters 185 13.2.3.2 Converting Short-Term Memory to Long Term 186 13.3 Animal Memory: Invertebrates 186 13.3.1 Discovery of the Signaling Contribution to Memory 186 13.3.2 Receptor Mechanisms of Nerve Cell Interactions 186 13.3.2.1 The GillWithdrawal Reflex of Aplysia 186 13.3.2.2 Mechanisms Underlying Sensitization and Short-Term Memory 187 13.3.2.3 Ion Flows in Nerve Action Potentials 187 13.3.2.4 Consolidation into Long-Term Memory (LTP) 188 13.4 Animal Memory: Vertebrates 188 13.4.1 Intracellular Mechanisms of Potentiation 188 13.5 Receptors and Behavior: Addiction, Tolerance, and Dependence 190 13.5.1 Opioid Receptors 190 13.5.1.1 Opioid Neuron Pathways in the Brain 191 13.5.1.2 The Opioid Peptides and Receptors 192 13.5.1.3 Mechanisms of Transduction 192 13.5.1.4 Characteristics of Responses to Continued Drug Presence 192 13.5.2 Individual and Cultural Distributions of Depression 193 13.5.2.1 Depression 193 13.5.2.2 Polymorphisms in Neurotransmitter Transporters 194 13.5.2.3 Polymorphisms in Opioid Receptor Subtypes 194 13.5.2.4 Polymorphisms in Enzymes for Transmitter Disposition 194 13.5.2.5 Society-Level Actions 194 13.5.2.6 Possible Mechanisms 195 14 Evolution of Receptors, Transmitters, and Hormones 197 14.1 Introduction 197 14.1.1 Phylogeny of Communication: General Ideas 197 14.1.2 The Receptors 197 14.2 Origins of Transmitters and Receptors 197 14.2.1 Evolution of Signaling Processes 197 14.2.2 Homologous Sequences 198 14.2.2.1 Orthologous and Paralogous Sequences 198 14.2.3 Phylogenetic Inference 199 14.2.4 Phylogenetic Illustration of Protein Relationships 199 14.2.5 Whole-Genome Duplication (WGD) 200 14.2.6 Origins of Novel Domains 201 14.2.7 Adaptation of Receptor Systems 201 14.2.8 Coevolution of Components of Signaling Pathways 202 14.2.9 Peptide Hormones and Their Receptors 202 14.2.10 Receptors and Their Non-Peptide Hormones 202 14.3 Evolution of Hormones 202 14.3.1 Peptide Hormones for G Protein-Coupled Receptors 202 14.3.1.1 The Yeast Mating Pheromones 203 14.3.1.2 The Anterior Pituitary Trophic Hormones 203 14.3.1.3 The Hypothalamic Releasing Hormones 203 14.3.1.4 The Posterior Pituitary Hormones 203 14.3.1.5 Miscellaneous Peptide Hormones 204 14.3.2 Hormones of the Receptor Tyrosine Kinases 204 14.3.2.1 The Insulin Family 204 14.3.2.2 The Neurotrophins 204 14.3.2.3 The Growth Hormone Family 204 14.4 Evolution of Receptor Superfamilies 205 14.4.1 Ion Channels 205 14.4.1.1 Voltage-Gated Channels 205 14.4.1.2 Ligand-Gated Channels 205 14.4.2 G Protein-Coupled Receptors 206 14.4.2.1 G-Protein-Coupled Receptor Types 206 14.4.2.2 Family A Receptors Rhodopsin Family 206 14.4.2.3 Family B Secretin and Adhesion Receptors 207 14.4.2.4 Family F Frizzled and Smoothened Receptors 208 14.4.2.5 Elements of the GPCR Transduction Pathway 208 14.4.3 The Immunoglobulin Superfamily 210 14.4.3.1 The Receptor Tyrosine Kinases 210 14.4.3.2 Molecules of the Adaptive Immune System 211 14.4.4 Steroid, Vitamin A/D, andThyroid Hormone Receptors 211 14.4.4.1 Origin of Nuclear Receptors: The Role of Ligands 211 14.4.4.2 The Nuclear Receptor Families 211 14.4.4.3 Later Evolution of Nuclear Receptors Ligand Exploitation 212 14.5 Evolution of Receptor Antagonism 213 14.6 A Final Note 213 Glossary 215 References 227 Index 241 |
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