- ISBN: 9783527337262 | 3527337261
- Cover: Paperback
- Copyright: 5/2/2016
This book is geared to every student in biology, pharmacy and medicine who needs to become familiar with receptor mediated signaling. The text starts with explaining some basics in membrane biochemistry, hormone biology and the concept of receptor based signaling as the main form of communication between cells and of cells with the environment. It goes on covering each receptor superfamily in detail including their structure and evolutionary context. The last part focusses exclusively on examples where thorough knowledge of receptors is critical: pharmaceutical research, developmental biology, neurobiology and evolutionary biology. Richly illustrated, the book is perfectly suited for all courses covering receptor based signaling, regardless whether they are part of the biology, medicine or pharmacology program.
Michael Roberts is Professor of Biology at Linfield College in McMinnville (Oregon, USA). He has taught biology to students for 40 years, first at Yale University and since 1981 at Linfield College. His scientific focus is cardiovascular physiology and the regulation of animal body temperature.
Anne Kruchten is Associate Professor of Biology at Linfield College in McMinnville (Oregon, USA). A graduate of the University of Minnesota, she joined Linfield College in 2006. Her scientific focus is the regulation of cell migration.
Anne Kruchten is Associate Professor of Biology at Linfield College in McMinnville (Oregon, USA). A graduate of the University of Minnesota, she joined Linfield College in 2006. Her scientific focus is the regulation of cell migration.
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 α Subfamily 99
7.4.1.2 The β Subfamily 102
7.4.1.3 The γ Subfamily 102
7.4.1.4 The δ 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-β) 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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