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Receptor Biology

by: Roberts, Michael S.; Kruchten, Anne E.

Receptor Biology

by: Roberts, Michael S.; Kruchten, Anne E.

ISBN 13:
9783527337262
ISBN 10:
3527337261
Edition: 1st
Format: Paperback
Copyright: 05/02/2016
Publisher: Wiley-VCH

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Receptor Biology > ISBN13: 9783527337262

Summary

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.

Author Biography

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.

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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