Michael F Roberts Anne E Kruchten Receptor Biology Michael F Roberts and Anne E Kruchten Receptor Biology Authors Michael F Roberts Linfield College Biology Department McMinnville 97128 Murdock 216 OR United States Anne E Kruchten Linfield College Biology Department 900 SE Baker Street 97128 McMinnville OR United States All books published by Wiley-VCH are carefully produced Nevertheless, authors, editors, and publisher not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Cover Frontcover picture: © Getty Images, ID 470751895 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at © 2016 Wiley-VCH Verlag GmbH & Co KGaA, Boschstr 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Print ISBN: 978-3-527-33726-2 ePDF ISBN: 978-3-527-80015-5 ePub ISBN: 978-3-527-80017-9 Mobi ISBN: 978-3-527-80016-2 Typesetting SPi Global, Chennai, India Printing and Binding Printed on acid-free paper To our mentors: Warren Porter, University of Wisconsin – Madison and David Bernlohr, University of Minnesota To our families: Mike Roberts Christopher Rosemary Yarrow Sherill Amelia Mike Kruchten John Paul Luis Anne VII Contents Acknowledgment XIII Part I 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 1.2 1.2.1 1.3 2.1 2.1.1 2.1.2 2.1.3 2.2 2.2.1 2.2.2 2.3 2.3.1 3.1 3.1.1 3.1.2 3.1.2.1 3.1.2.2 Introduction Introduction Receptors and Signaling General Aspects of Signaling Verbal and Physiological Signals Criteria for Recognizing Transmitters and Receptors Agonists Receptors Receptor–Enzyme Similarities Types of Receptors and Hormones Receptor Superfamilies Receptors Are the Chemical Expression of Reality The Origins of Chemical Thinking Overview of Early Pharmacological History The Development of a Chemical Hypothesis Chemical Structure and Drug Action 10 The Site of Drug Action 10 Modern Pharmacology 10 Langley and Ehrlich: the Origins of the Receptor Concept 10 Maturation of the Receptor Concept 13 Phylogenetics of Signaling 13 The First Communicators 13 Part II 3.1.2.3 3.1.2.4 3.1.3.3 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 4.1 4.1.1 4.2 4.2.1 4.2.2 4.2.3 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.3 Fundamentals 15 Membranes and Proteins 17 Membranes 17 The Cytoplasmic Membrane – the Importance of Cell Membranes 17 History of Membrane Models 17 The Roles of Proteins in Membranes Challenges to the Danielli–Davson Model 19 3.1.3 3.1.3.1 3.1.3.2 18 4.3.1 4.3.1.1 4.3.1.2 4.3.2 4.3.2.1 A New View of Membrane Proteins 19 The Modern Concept of Membranes – the Fluid Mosaic Model 19 Membrane Components 19 Membrane Lipids 19 Asymmetry and Heterogeneity in Membrane Lipids 20 Membrane Construction and Insertion of Proteins 20 The Nature and Function of Proteins 21 Linear and Three-Dimensional Structures 22 Primary Structure 22 Secondary Structure 23 Tertiary Structure 24 Protein Domains 25 Proteomics 25 27 Hormones and Cellular Communication 27 Discovery of Hormones 27 Types of Hormones 27 Pheromones for Signaling between Individuals 28 Archaea and Bacteria 28 Eukaryotes 29 Chromalveolates 29 Unikonts – Amoebozoa, Fungi, Animals 29 Invertebrate Pheromones 31 Vertebrate Pheromones 31 Vertebrate Hormones and Transmitters 31 Peptide and Non-Peptide Agonists 31 Peptides 31 Non-peptides 31 Peptide Hormones of the G-Protein-Coupled Receptors 32 Hypothalamic-Pituitary Axis 32 Hormones as First Messengers VIII Contents 4.3.2.2 4.3.3 4.3.3.1 4.3.3.2 4.3.4 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.3.5 4.3.5.1 4.3.5.2 4.3.5.3 4.3.6 4.3.7 4.3.7.1 4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5 4.3.8 4.3.8.1 4.3.8.2 4.4 The Anterior Pituitary Trophic Hormones 34 Other Neural Peptides 35 Opioids 35 Non-Opioid Transmitter Peptides 36 Peptides from Non-Neural Sources 36 Digestive Tract Hormones 36 Hormones from Vascular Tissue 38 Hormones from the Blood 38 Peptide Hormones from Reproductive Tissues 39 Hormones from Other Tissues 39 Non-Peptides Acting on G-Protein-Coupled Receptors 39 Transmitters Derived from Amino Acids 39 Transmitters Derived from Nucleotides 40 Transmitters Derived from Membrane Lipids – Prostaglandins and Cannabinoids 41 Transmitters of the Ion Channels 41 Hormones of the Receptor Kinases – Growth Factor Receptors 43 Insulin 43 Insulin-Like Growth Factors 43 Natriuretic Peptides 43 Peptide Signal Molecules Important in Embryogenesis 43 Pituitary Gland Hormones – Somatotropin and Prolactin 43 Hormones of the Nuclear Receptors 44 Steroids 44 Non-Steroid Nuclear Hormones 46 Analgesics and Venoms as Receptor Ligands 46 Receptor Theory 47 5.1 5.2 5.2.1 5.2.1.1 5.3 5.3.1 The Materialization of Receptors 47 Receptor Mechanisms 47 Binding of Agonist to Receptor 48 Bonds 48 Binding Theory 49 Early Approaches to Understanding Receptor Action 49 The Occupancy Model 49 Processes That Follow Receptor Activation 52 Efficacy and Spare Receptors 52 Modern Approaches to Receptor Theory 52 The Two-State Model 52 5.3.1.1 5.3.1.2 5.3.1.3 5.3.2 5.3.2.1 5.3.2.2 5.3.2.3 5.3.2.4 5.3.3 5.4 5.4.1 5.4.1.1 5.4.2 5.4.2.1 5.4.2.2 5.4.2.3 5.4.3 5.4.4 5.5 5.6 5.6.1 5.6.2 The Ternary Complex Model 53 Protean Agonism 54 Cubic Ternary Complex (CTC) Model 55 Summary of Model States 55 Visualizing Receptor Structure and Function 55 Determination of Receptor K d 55 Schild Analysis 56 Visualizing Ligand Binding 57 Receptor Preparation 58 Equilibrium Binding Studies 58 Competition Studies 58 X-ray Crystallography of Native and Agonist-Bound Receptors 59 Probe Tagging (Fluorescent and Photoaffinity) 60 Proteomics Approaches to Receptor Efficacy 60 Physical Factors Affecting Receptor Binding 61 Temperature 61 Relation of Agonist Affinity and Efficacy to Distance Traveled Following Release 61 Part III Receptor Types and Function 63 Transduction I: Ion Channels and Transporters 65 6.1 6.1.1 6.2 6.2.1 6.2.2 6.2.2.1 Introduction 65 Family Relationships 65 Small Molecule Channels 66 Osmotic and Stretch Detectors 66 Voltage-Gated Cation Channels 66 History of Studies on Voltage-Gated Channels 66 Structure and Physiology of Ion Channels 68 Potassium Channels 68 Sodium Channels 70 Bacterial Na+ Channels 70 Vertebrate Na+ Channels 70 Calcium Channels 71 Non-Voltage-Gated Cation Channels – Transient Receptor Potential (TRP) Channels 72 Transporters 73 Pumps and Facilitated Diffusion 73 The SLC Proteins 73 The Pumps 74 The Chloride Channel 76 6.2.2.2 6.2.3 6.2.4 6.2.4.1 6.2.4.2 6.2.5 6.2.6 6.3 6.3.1 6.3.1.1 6.3.1.2 6.3.2 References 394 Ganfornina, M.D., Sánchez, D., and Bastiani, M.J 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 (1996) The role of the cell surface in neuronal pathfinding Bioscience, 46 (5), 344–354 Sperry, R.W (1963) Chemoaffinity in the orderly growth of nerve fiber patterns and connections Proc Natl Acad Sci U.S.A., 50, 703–710 Raff, M.C (1992) Social controls on cell survival and cell death Nature, 356 (6368), 397–400 Koonin, E.V and Aravind, L (2002) Origin and evolution of eukaryotic apoptosis: the bacterial connection Cell Death Differ., (4), 394–404 Clarke, P.G.H (1985) Neuronal death in the development of the vertebrate nervous system Trends Neurosci., 8, 345–349 Micheau, O and 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the melanocortin receptor in vitro and in vivo Genes Dev., 12 (3), 316–330 241 Index a acetylcholine (ACh) 28 adhesion receptors, family 106 adrenocorticotropic hormone (ACTH) 33, 35, 128, 129 agonist agonist binding, receptors – cellular activation 48 – hydrogen bonds 48 – ionic bonds 48 – reversible 48 – selectivity 48 – stabilization 48 – types, bonds 48 – van der Waals forces 48, 49 agonist occupancy equation 56 ancestral steroid receptor 123 angiotensin II 38 animal memory – invertebrates – – nerve cell interactions 186–188 – vertebrates – – signaling contribution discovery 186 – – hippocampal pathway 188 – – potentiation, intracellular mechanisms 188, 189 – – presynaptic cell 184 antidiuretic hormone (ADH) 32 apoptosis 129 – adult life 166 – bacteria 165 – definition 165 – during development 166 – maladaptive practice 165 – mitochondrial origin 165 – proteins 165 arrestin –GRK system 97 ATP-binding cassette (ABC) 41 autoinducer (AI) 28 b bacterial short-term memory – intracellular pathways 181 – learning 181 – nutrient gradients 182 – receptor-based environmental adaptations – signaling systems 182 182 bacteriorhodopsin 85 binding theory – agonist concentration and receptor occupation 49 – GPCRs 49 – Langley’s concept 49 – occupancy model 49–51 – physical factors – – agonist affinity 61 – – Clark’s model 51 – – ion channel agonist binding and activation 53 – – nicotinic ACh receptor 48 – – receptor occupancy and response 52 – – smooth muscle contractions 50 – – temperature 61 – – tissue response, hormone/neurotransmitter 51 bone morphogenetic protein (BMP) 43 biological communication brain-derived neurotrophic factor (BDNF) 175 brain transmitters – amino acids/amines 184 – peptidergic neurons 184 – facilitation circuit, Aplysia 187 – peptides 184 – phyletic distribution 185 – short-term into long-term memory 186 – presynaptic facilitation, Aplysia cAMP mechanism 189 – synthesis and release 185 – synthesis and transport 186 c Ca-binding protein calmodulin 72 calcium channels – cardiac pacemakers 71 – contractile process 72 – depolarization 72 – electrical excitability 71 – L-type channels 71 cAMP-related binding protein (CREB) 175 cancer – signaling molecules 178 – pathogenesis 177 – – Hedgehog –Patched –Smoothened 178 – – IGF 178 – – mitogenic factors 178 – – oncogenes, see oncogenes Receptor Biology, First Edition Michael F Roberts and Anne E Kruchten © 2016 Wiley-VCH Verlag GmbH & Co KGaA Published 2016 by Wiley-VCH Verlag GmbH & Co KGaA 242 Index cancer (contd.) – – phosphorylation 178 – – transcription regulators 178 – – transducing proteins 178 cannabinoid receptors (CRBs) 102 carbon monoxide (CM) 147 cascade-like processes 135 cell aggregation–in bacteria 140 – CAMs 140 – – cadherins 141 – – development, role in 141 – – glycoproteins 141 – in eukaryotes – – homophilic binding 140 – – sponges 140 cell-adhesion molecules (CAM) 140 – cadherins 141 – development, role in 141 – glycoproteins 141 cell-free biochemical systems 58 cell-surface molecules – antigen 117 – cytokine receptors 117 – MHC proteins 117 – T and B cells – – CD molecules 118 – – interleukin-1 118 – – plasma cells 118 cell-surface receptors 4, 121 cell theory cellular communication – receptor, see receptor – signaling – – organismal cell signaling – – verbal and physiological signals – – agonists – – ligand chemoaffinity hypothesis 164 chemoreception – mammals – – evolutionary pathway 89 – – odors 87 – – taste 87 – – visual sense 87, 88 – non-mammals – – cyclic AMP 87 – – insect gustation 87 – – odor sensing 87 chloride channels 76 cholecystokinin (CCK) 36 chorionic gonadotropin (CG) 39 Clark’s hypothesis 51 classical receptor 121 clonal selection theory 116 cluster of differentiation (CD) molecules Cnidarians – diffusion, transmitters 182 – intracellular organelles 183 – neural net pattern, organization 182 – neurosecretory 182 – peptide neurohumors 182 – sensory receptor cells 182 corticosteroids 131 corticotrophin-releasing hormone (CRH) 33, 126, 203 cubic ternary complex model 55, 56 cyclic adenosine monophosphate (cAMP) 29, 131 cyclic AMP (cAMP) receptors 106 cyclooxygenase (COX) 41 cystic fibrosis 172 cystic fibrosis transmembrane regulator (CFTR) 75, 172 cytoplasmic polyadenylation element binding (CPEB) 185 d Danielli –Davson model 18, 19 depression – behavioral differences 193 – directional selective pressure 195 – human individuality 193 – learning and mood 193 – MAOA-uVNTR allele, monoamine oxidase – mood-related pathways 193 – polymorphisms – – enzymes, transmitter disposition 194 – – neurotransmitter transporters 194 – – opioid receptor subtypes 194 – psychological differences 195 – receptor mechanism, addiction 193 – society-level actions 194, 195 – transmitter disposition 193 deuterostomes – early frog development 162 – evolution 151, 153 – nerve growth – – address selection 165 – – CNS 164 – – ligand –receptor interactions 164 – – pathway selection 164 – – target selection 165 Development – mammalian fertilization – – acrosomal reaction 157 – – egg surface proteins 157 – – late events 158 – – metabolic activation 157 – – sperm surface proteins 157 – sperm –egg recognition – – sea urchin, see sea urchin fertilization – – in vitro fertilization techniques 154 DNA sequences 85, 198 195 e 118 endocannabinoid (eCB) signaling 103 endocannabinoids 41 endoplasmic reticulum (ER) 20 endothelin 38 enzyme –substrate interactions 48 epidermal growth factor (EGF) 111, 154 epinephrine (EP) 13 epithelial channels (ENaC) 71 Erwinia ligand-gated ion channel (ELIC) 79 evolution, receptors, transmitters and hormones – duplication and mutational divergence 198 – history 197 – homologous sequences 198, 199 – hormone signaling systems 197 Index – non-peptide ligands 202 – orthologous and paralogous sequences 198 – peptide hormones and receptors 202 – phylogenetic inference 197, 199 – protein relationships 199–201 – phylogeny, communication 197 – receptor systems adaptation 201, 202 – signaling processes 197, 198, 202 – whole-genome duplication 200 excitatory transmitters 42 extracellular matrix (ECM) 144, 164 f familial hypercholesterolemia (FH) 176 fibroblast growth factor (FGF) 111, 161 first messengers 27 fluid mosaic model 19 follicle-stimulating hormone (FSH) 35 frizzled-smoothened receptor, family 106 g G proteins – β–γ subunits 91, 92, 94, 95 – adenylyl cyclase 92 – – ion channel activation 96 – – transmitter release inhibition 96 – – membrane-bound effector proteins 95 – G-alpha proteins 92 – Gs activation 98 – hormonal signal transduction 91 – ion channels 92 – ligand binding 98 – MAP kinases 95 – molecular structure 91 – phospholipase C (PLC) activation 93–95 – protein kinase activation 93–95 – radiolabeled GTP analogs 93 – and receptors interactions 97, 98 – regulatory kinases 91 – Ras 95 – transducin, visual system 92 – vertebrate vision 93 G-protein-coupled receptors (GPCR) 29, 121, 138 – adenylyl cyclase, stimulation/inhibition 86 – Archaeal and Eukaryotic rhodopsin 206 – anterior pituitary trophic hormones 34 – bacterial rhodopsin 206 – bacteriorhodopsin 86 – cardiac and smooth muscle contraction 85 – cell process stimulation 99 – cell surface expression 86 – cellular metabolism 85 – cylindrical transmembrane domains 86 – dimerization 86 – families, sequence homologies 89, 90 – functional domains 98 – G(uanine nucleotide binding) proteins 85 – GDP –GTP 138 – hormone secretion and sensation 85 – hormone/transmitter binding 86 – in eukaryotes 85 – hypothalamic-pituitary axis – – hypothalamic hormones 32 – – RH 32 – inositol-1,4,5-trisphosphate receptor 94 – insect taste receptors 106 – ligand binding 85 – invoking G proteins, criteria of 139 – ligand-activated catalytic cascade 97 – mating types, haploid yeast cells 106 – membrane topology 105 – membrane-bound transducer protein 86 – metabotropic 86 – nematode chemoreceptors 106 – neuropeptides, β 209 – pharmaceutical industry 85 – phosphatidylinositol transduction cycle 94 – receptor interactions 85 – Ran 139 – Ras 139 – receptor internalization 86 – receptor maturation 86 – receptors control visceral functions 85 – secretin and adhesion – receptors-rhodopsin family – – α class 206 – – amine receptors 207 – – β class 207 – – δ class 207 – – γ class 207 – – prostanoid receptors 207 – – elongation factors 208 – – C-metabotropic glutamate 208 – – frizzled and smoothened receptor 208 – – parathyroid hormone 207 – – transduction system 208 – – oncogene and G proteins 209 – – vertebrate and invertebrate lineages 208 – sensory transduction, see Sensory transduction – signaling systems 87 – superfamily 207 – transducer and effector proteins 92 – – amino acids 39 – – cannabinoids 41 – – nucleotides 40 – – prostaglandin 41 – – cAMP 206 – – frizzled/smoothened receptors 206 – – fungal pheromone receptors 206 – – metabotropic glutamate receptors 206 – – rhodopsin-like 206 – – secretin-like 206 – vertebrate retina, rod cell 93 – yeast mating pheromone receptors 106 gamma-amino butyric acid (GABA) 38, 152 gamma-amino butyric acid, type A (GABAA ) 131 gastrin 38 gene duplication 212 ghrelin 38 genome 25 glucagon 38 glucocorticoid receptor (GR) 212 glycerol transporters 77 gonadotropin-releasing hormone ( GnRH) 34, 203 growth hormone (GH) 34 growth hormone inhibiting hormone 34 growth-hormone-releasing hormone (GHRH) 34, 203, 204 243 244 Index h i heat shock protein (HSP) 124 hepatocyte nuclear factor (HNF) 121 Hedgehog gene 161 heterodimers 125 hormone response element (HRE) 122, 125 hormones – analgesics and venoms 46 – discovery 27 – first messengers 27 – GPCR, see G-protein-coupled receptors (GPCR) – growth factor receptors – – IGF 43 – – insulin 43 – – natriuretic peptide 43 – – peptide signal molecules 43 – – prolactin and placental lactogen 44 – – somatotropin 43 – intracellular signal 27 – neural peptides – – non-opioid transmitter peptides 36 – – opioids 35 – non-neural peptides – – angiotensin II 38 – – bradykinin 38 – – CCK 36 – – endothelins 38 – – gastrin 38 – – ghrelin 38 – – glucagon 38 – – NM-B 39 – – reproductive tissues 39 – – secretin 38 – non-peptides agonist 31 – nuclear receptors – – non-steroid 46 – – steroids 44 – peptides agonist 31 – second messenger 27 – transmitters – – amino acids 39 – – cannabinoids 41 – – ion channels 41 – – nucleotides 40 – – prostaglandin 41 – types of organisms 28 – – animals 29 – – archaea and bacteria 28 – – chromalveolates 29 – – fungi 29 – – invertebrate pheromones 31 – – pheromone 28 – – Unikonts –Amoebozoa 29 – – vertebrate pheromones 31 human communication hydrogen sulfide (H2 S) 148 hypothalamic releasing hormones (RH) – CRH 33 – GHRH 34 – GnRH 34 – SS28 34 – TRH 34 hypotheses immunoglobulin superfamily – extracellular cysteine-rich regions 210 – adaptive immune system 211 – immune system responses 210 – intracellular kinase domain 210 – phosphorylation 210 – RTKs 210 – types, receptor kinases 210 inhibitory transmitters 42 insect taste receptors 106 insulin 43 insulin receptor (INS) – FGF 111 – function 111 – PDGF 111 – NGF 111 insulin-like growth factor (IGF) 43, 178, 204 interstitial-cell-stimulating hormone (ICSH) 35 intracellular signal 27 ion channel superfamily – bacterial K+ -selective glutamate channels 205 – cystic fibrosis transmembrane regulator 205 – ligand-gated 205, 206 – stretch- and osmotic shock-gated channels 205 – vertebrate K+ channels 205 – voltage-gated 205 ion channels and transporters – active transport 65 – aquaporins 77 – family relationships 65, 66 – GABAA receptor 80 – glutamate transporter model 74 – metabolism 65 – nAChR, muscle 80 – NMDA receptor 82 – P2X peptide orientation 83 – passive facilitated diffusion 65 – taste transduction 73 – transmembrane active transport pumps 75 – voltage gated and ligand gated 65 j Janus kinase (JAK) 144 l last universal common ancestor (LUCA) 14 leptin 174 ligand ligand binding visualization – binding studies 58 – competition studies 58 – equilibrium binding studies 58 – radioactive atoms 57 – radiolabeled ligands binding 57 – receptor binding processes 58 – receptor type distribution 58, 59 ligand exploitation 202 ligand-gated ion channels (LGICs) – anions, TM – – amine-gated Cl- chanels 81, 82 – – benzodiazepines 81 – – gamma-amino butyric acid (GABA) receptor 80 Index – – glycine receptor 81 – – histamine receptors 81 – ATP-gated receptor, TM – – cell integrity 83 – – inflammation detection 83 – – neural activity modulation 83 – – neuronal P2X receptors 82 – – signaling processes 83 – – single-celled chlorophyte alga 83 – – skeletal, cardiac and smooth muscles contraction 83 – chemotaxic molecules 77 – ELIC protein 79 – ionotropic glutamate receptors, TM 77 – – glutamate-gated channels 82 – – N-methyl-D-aspartate (NMDA) receptor 82 – – non- NMDA receptors 82 – ionotropic serotonin (5HT3) receptor 80, 81 – TM, cations – in metazoan animals 77 – – α –γ subunits 78 – – electric fish acetylcholine receptors, shock generators 79 – – ACh 78, 79 – – autonomic ganglia 78 – – bacterial channels 79 – – cysteine –cysteine disulfide link 77 – – Dendrobatidae 81 – – ligand-binding sites 78 – – muscle-type and nerve-type nAChRs 79 – – nerve-type receptors 79 – – nicotinic receptors 78 – – voltage gradients 79 – – voltage-gated channels 79 local modulators 27 low-density lipoprotein (LDL) 114, 176 – apo B 114 – domains 114 – clathrin-coated pits 114 luteinizing hormone (LH) 34 m major histocompatibility (MHC) 108, 117 mathematical approaches, modeling 47 mating-type alpha (MAT) 30 membranes – cytoplasmic membrane 17 – lipids – – asymmetry and heterogeneity 20 – – cholesterol 20 – – construction and insertion of protein 20 – – phospholipid membrane 19 – – sphingolipids 20 – membrane models – – Danielli and Davson’s model 19 – – hydrophobic 19 – – fluid mosaic model 19 – – history of 17 – – hydrophilic 19 – – protein, role of 18 metabotropic glutamate receptors (mGluRs) – calcium-sensing 106 – dimerization type 105 – taste receptors 105 mineralocorticoid receptor(MR) 212 mitogen-activated protein kinase (MAPK) 136, 146 multicellular body plan multicellular lineages – in eukaryotes – – amoebozoans 151 – – animals 151 – – archaeplastida 151 – – choanoflagellates 151 – – chromalveolates 151 – – fungi 151 – – taxa 150 – in prokaryotes 150 muscle-electroplax nicotinic Ach receptor 80 n natriuretic peptide (NP) 43 natriuretic peptide receptor (NPR) 112 nematode chemoreceptors 106 nerve cell interactions – Aplysia, gill withdrawal 186, 187 – habituation 187 – ion flows, nerve action potentials 187, 188 – long-term memory consolidation 188 – sensitization and short-term memory 187 nerve growth factor (NGF) 111, 165 nervous systems – diffuse nerve network comparisons 182 – neuron – – cell structure 183 – – mechanisms 184 – organization 183 – transmitters, see brain transmitters neuromedin-B (NM-B) 39 neuropeptide Y (NPY) 38 neurotransmitter 27 neurotrophins 43 nitric oxide (NO) 147 non-voltage-gated cation channels 72 Notch–Delta pathway 152 Notch–Delta signaling 115 nuclear receptors – agonists 121 – antagonists 121, 129 – genomic actions – – DNA-binding module 125 – – androgens 128 – – estrogen 128 – – families of 122 – – glucocorticoid steroid hormone 128 – – HNF4 122, 127 – – insect metamorphosis 127 – – mineralocorticoid 129 – – ligand-binding module 124 – – liganded receptors 122 – – multicellular heterotrophic lifestyle 122 – – progesterone 128 – – retinoic acid receptor 125 – – receptor structure 123 – – RXR 127 – – thyroid hormone 127 – – steroid receptor studies 123 – – thyroid receptor 125 – – transcription repression complexes 127 245 246 Index nuclear receptors (contd.) – – transcription control 122 – – vitamin A receptor 125, 127 – – vitamin D receptor 125, 127 – hydrophilic cellular proteins 121 – hydrophobic fatty acids 121 – steroid hormone action – – androgens 131 – – concept of 130 – – estrogen 131 – – mineralocorticoid 131 – – glucocorticoid 131 – – nongenomic effects 130 – – progesterone 131 – – thyroid hormone 131 – – transcription, ligand-independent osmotic detectors – and stretch 66 – structural/sequence homologies oxytocin 32 66 p 131 o occupancy model – agonist binding vs tissue activation 51 – agonist concentration and fraction of receptors 51 – allosteric proteins 53 – cellular action 52 – cellular/biological mechanism 49 – competitive antagonists 52 – dose –response curve 50 – drug propranolol 52 – efficacy and spare receptors 52 – experimental approaches, isolated tissues 50 – hypertensive effects, epinephrine 52 – law of mass action 49 – maximal binding 51 – nonlinear relationship, receptor occupancy and tissue response 51 – partial agonists 52 – plant substance atropine 52 – receptor binding 51 – response vs agonist 51 – theoretical development 49 – tissue activation 51 oncogenes – G protein 179 – transcription factors –steroid receptors – RTKs 178 – – breast cancer 180 – – estrogen and progesterone 180 – – receptor-positive and receptor-negative breast cancers 180 – – TNBC 180 – transmitters 178 opioids – analgesic drugs 190 – Auerbach’s plexus 191 – endogenous pathway, pain perception reduction 191 – mechanisms of transduction 192 – morphine-like drugs 191 – neuron pathways, brain 191 – pain-reducing neurotransmitters 190 – and opiates 190 – peptides and receptors 192 – physiological properties 190 – radiolabeled substances 190 patch clamp method 68 Patched gene 161 peptide hormones – bombesin 204 – anterior pituitary trophic hormones 203 – gastrin-releasing peptide 204 – gastrin and CCK 204 – hypothalamic releasing hormones 203 – neuromedin-B 204 – posterior pituitary hormones 203 – secretin 204 – yeast mating pheromones 203 – and receptors – – neofunctionalization 202 – – null mutation 202 – – subfunctionalization 202 pharmacological history – chemical hypothesis – – drug isolation – – non-experimental worldview – – mind -body dualism – – non-material worldview – – non-molecular worldview – drug action 10 – Mendeleev’s periodic chart 10 – organic chemistry – phylogenetics – – biological functions 14 – – domains of life 14 – – evolution of 14 – – multicellularity evolution 14 – – side chain hypothesis 12 – – quorum sensing 14 – – single-celled organisms 13 – – social behavior control mechanism 13 – – transporter and ion channel group 14 – receptor concept – – Bernard’s experiments 12 – – autonomic nervous system 12 – – cell-surface molecule 10 – – cell-surface receptive substances 12 – – direct electrical stimulation 12 – – lock and key mechanism 10 – – maturation 13 – – pilocarpine 10 – – receptive substance 12 – – postsynaptic nerve cells 12 – – preganglionic motor nerves 12 – – specific binding processes 10 – – signal transduction mechanism 12 – – trypanosome parasites 12 pheromone 28 phosphatidylinositol transduction cycle 94 phosphofructokinase (PFK) 144 phospholipid 19 phylogenetic relationships – bombesin 204 Index – gastrin-releasing peptide 204 – neuromedin-B 204 – NGF, BDNF and NT proteins 205 – prostanoid receptors and G protein 208 – voltage-gated ion channels 205 physical chemistry, binding processes 47 phytocannabinoids 41 platelet-derived growth factor (PDGF) 111, 178 potassium channels – classification 69 – families and subfamilies 68 – G-protein-linked inward rectifying channels 70 – K+ passive leak channels 69 – long water-filled channel 69 – in prokaryotes 68 – selectivity filter 68, 70 – voltage sensors 69 – X-ray crystallography 69 preproinsulin 43 pro-opiomelanocortin (POMC) 33 probe tagging – epibatidine 60 – fluorescent tags 60 – photoaffinity labeling 60 – UV irradiation 60 programmed cell death, see apoptosis prolactin-releasing hormones 203 prostaglandin (PG) 41 prostaglandin receptors, effectors and actions 102 protean agonism 54 protein kinase B (PKB) 142 proteins – secondary structure – domain 25 – linear structure 22 – primary structure 22 – proteomics 25 – – alpha helix 24 – – beta sheet 24 – – disulfide bridge 24 – – glycosylation 23 – – group interactions 23 – – higher order structures 24 – tertiary structure 24 proteomics proteome 25 – cellular effectors 61 – receptor function (efficacy) 60 psychosis 175 q quorum sensing 14, 28 r radioligand binding 47 receptor antagonism evolution 213 Rat Sarcoma (Ras) 139 Ras-related Nuclear proteins (Ran) 139 receptor – mechanisms – chemical expression of – receptor-enzyme similarities – superfamily – – classes – – in cellular processes – – fossil record – – growth factor – – properties – – intracellular receptors – – ion channels – – norepinephrine – – receptor kinases receptor antagonism evolution 213 receptors and mind – animals with neural networks 182 – animals without true neural organization, orifera 182 – bacterial short-term memory 181 – bilaterally symmetrical animals 183 – nervous systems, see nervous systems – opioid receptors, see opioids receptor kinases – adaptive immunesystem 116 – cell receptors 116 – cell-surface molecules, see cell-surface molecules – – antibodies 117 – – T and B cells 118 – cell –cell contact signaling 115 – cholesterol transport 113 – immunoglobulins 116 – innate immune responses 115 – LDL 114 – – apo B 114 – – clathrin-coated pits 114 – – domains 114 – NPR 112 – protein kinases 107 – RTK – – core processes 108 – – EGF 111 – – extracellular domains 108 – – features 108 – – INS, see insulin receptor (INS) – – subfamilies 108 – – intracellular domains 109 – TGF-β 112 receptor mechanisms, in disease processes – cellular alteration 169 – classical dominance mechanisms 169 – gene expression 170 – genotype 169 – phenotype 169 – post-receptor mutations 171 – pre-receptor mutations 170 – receptor mutations 171 receptor pathologies – calcium channels 172 – channelopathies 171 – chloride transporter 172 – immunoglobulin superfamily – – atherosclerosis 176 – – diabetes mellitus 176 – ligand-gated Na+ channels 172 – nuclear receptor superfamily – – antagonism 177 – – ERs 177 – – gender bending 177 – – transcription 176 247 248 Index receptor pathologies (contd.) – voltage-gated Na+ channel 172 – protein-coupled receptor superfamily – – cardiovascular disease 173 – – cholera 172 – – depression 175 – – obesity 174 – – schizophrenia 175 – – thyroid diseases 173 – TRP channels 172 receptor serine 107 receptor theory – agonists 47 – antagonists 47 – cellular processes 47 – equilibrium binding experiment 58 – GTPase activity 55 – interference patterns, inorganic crystal 60 – materialization 47 – mechanisms 47 – neutral (competitive) antagonism 55 – protean agonism 56 – radiolabeled compounds 57 – radiolabeled ligands binding 57 – Schild analysis 56, 57 – S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine (S-3-PPP) 55 – two-state model 52, 53 receptor tyrosine kinase (RTK) 35, 107, 108, 110, 122, 210 – core processes 108 – EGF 111 – extracellular domains 108 – features 108 – INS – – FGF 111 – – function 111 – – NGF 111 – – PDGF 111 – subfamilies 108 – intracellular domains 109 – signaling complexity 144 receptor-activity-modifying-protein 104 receptors and mind – animals with neural networks 183 – bacterial short-term memory 181, 182 – behavioral complexity 181 – decentralized nerve networks 181 – protostomes and deuterostomes 183 – vertebrate neural organization 181 relaxin 39 retinoic acid (RA) 127 retinoic acid receptor (RAR) 125 retinoid X receptor (RXR) 127 rhodopsin-like, family – α subfamily – – adenosine receptors 101 – – alpha-adrenoceptors 100 – – beta-adrenoceptors 99, 100 – – CBRs 102 – – dopamine receptors 100 – – histamine receptors 100 – – monoamine receptors 99 – – muscarinic receptors 100, 101 – – P2Y receptors 101 – – – – – – – – – – – – – – prostaglandin receptors 102 – purine and pyrimidine nucleotides receptors – serotonin receptors 100 – TAARs 101 β subfamily 102 δ subfamily – bitter receptors 104 – evolutionary history of eyes 89 – olfactory molecules 104 – taste receptor 104 γ subfamily – opioid receptors 103 – peptide venom receptors 103, 104 101 s sea urchin fertilization – egg surface 154 – egg surface receptor 156 – – early events 156 – – late events 156 – – protein-coupled receptor action 157 – sperm activation and chemotaxis 154 – sperm surface proteins 154 second messenger 27 secretin 38 secretin-like, family 104 selective progesterone receptor modulator (SPRM) 130 selective receptor modulator (SRM) 130 sensory transduction – amplification 97 – cell-membrane receptors 87 – cessation 97 – chemo- and visual-sensory receptor mechanisms 87 – chemoreception, see chemoreception – cyclase-inhibitory receptor 92 – cyclic AMP discovery 90 – desensitization 97 – G proteins discovery 90 – GAP proteins 96 – GEF proteins 96 – hormone/neurotransmitter signaling systems 87 – inactivation 97 – metabolic activation process 89, 90 serotonin 175 signal transducer and activator of transcription (STAT) 144 signaling complexity – cytokine receptors 144 – gas molecules – – CO 147 – – H2 S 148 – – NO 147 – glycolysis 135, 142 – in cancer – – constitutive vs inducible activation 144 – – disregulation 144 – – low-level constitutive cascade activity 146 – integrins 144 – JAK 144 – MAPK 136, 146 – PFK 144 – PIP3 142 – PKB 142 – RTKs 144 Index – STAT 144 – transduction – – cell aggregation, see cell aggregation – – GPCR, see G-protein-coupled receptors (GPCR) – – ion channel 138 – – non-receptor proteins 138 site-directed mutagenesis 47 social behavior control mechanism 13 sodium channels – bacterial 70 – vertebrate – – ENaC 71 – – neuronal 70, 71 – – voltage sensor 71 somatostatin 28 (SS28) 34 static lock-and-key mechanism of Fischer 52 steady-state (equilibrium) binding experiments 58 steroid receptors, nuclear receptor – evolution, ligand exploitation 212 – families 211, 212 – ligand 211 sweet/umami taste receptors 104–106 symmetry and axes, origin of – Cnidaria 153 – mesoderm 154 – multicellular body plan 152 – sponges 152 t ternary complex model 53, 54 tetrahydro-cannabinol (THC) 41 threonine kinases 107 theory of evolution Thyroid hormone 46 thyroid receptor (TR) 125, 127 thyroid-stimulating hormone (TSH) 34, 126 thyrotropin-releasing hormone (TRH) 34, 203 thyroxine hormone (TH) 126 trace-amine-associated receptors (TAARs) 101, 131 transduction, G-protein-coupled receptors (GPCR) – cAMP receptors 99 – frizzled/smoothened receptors 99 – fungal pheromone receptors 99 – GRK and β-arrestin 99 – metabotropic glutamate receptor 99 – rhodopsin-like family 99 – secretin-like family 99 transforming growth factor (TGF) 43 transforming growth factor-beta (TGF-β) 112 transient receptor potential (TRP) channels 72, 73 transient receptor protein (TRP) 172 transporters – ClC channels, see chloride channels – pumps and facilitated diffusion – – ABC transporters 74 – – ATP-powered pumps 74 – – cystic fibrosis 74 – – SLC proteins 74 – – translocation 74 triple negative breast cancer (TNBC) 180 triploblastic embryos –organogenesis – drosophila – animals 158 – bilateria 158 – deuterostomes, development in, see deuterostomes – – developmental receptors 160 – – pharmacological receptors 160 – – eye 162 – – dorsal and ventral sides 159 FGF 161 – – front and hind ends 159 – – induction 160 – – heart formation 161 – – nuclear division 159 – – pharmacological receptors 160 – – respiratory tract 162 – gastrulation 158 – induction 158 – ligand –receptor interactions 158 tropic 34 tropins 34 tyrosine kinases – growth hormone (GH) 204 – insulin family 204 – phylogenetic relationships 204 v V-type (vacuolar) pumps 74 vasopressin 32 venomous lizards 103 vectorial discharge 21 vertebrate evolution, nuclear steroid receptor family 213 visual pigment rhodopsin 88 Vertebrate metamorphosis 126 vitamin 46 vitamin A receptor (VitAR) 125 vitamin D receptor (VitDR) 125 voltage-gated cation channels – action potential 67 – agonist concentration 67 – bacterial 70 – choanoflagellates 66 – intracellular voltages 67 – ion channels 67 – ion movements 67 – KcsA channel –organization 69 – nerve activation process 67 – patch clamping 67 – structural/sequence homologies 66 – structure and physiology 68 – synaptic transmission 67 – ventricular cell 72 – vertebrate 71 – voltage sensing channels 66 w water channels – aquaporins 76, 77 – balance, kidney 77 – electric fish 79 – and functions 77 – kidney matrix 77 – membrane proteins 76 – in mammals 77 – multimeric proteins 76 – type channels 77 water-soluble hormones 28 249 250 Index x x-ray crystallography – atomic structure analysis 60 – bond angles and lengths 59 – constructive wave 60 – inorganic crystals 60 – molecular size measurement 59 – photographic/digital surface 60 – recording devices 60 – x-ray slice, enzyme molecule 60 y yeast mating pheromone receptors z zinc finger motif 125 106 WILEY END USER LICENSE AGREEMENT Go to www.wiley.com/go/eula to access Wiley’s ebook EULA ...Michael F Roberts Anne E Kruchten Receptor Biology Michael F Roberts and Anne E Kruchten Receptor Biology Authors Michael F Roberts Linfield College Biology Department McMinnville 97128 Murdock... Biology Department McMinnville 97128 Murdock 216 OR United States Anne E Kruchten Linfield College Biology Department 900 SE Baker Street 97128 McMinnville OR United States All books published by... sabbatical research in Belgium Numerous colleagues at the Mayo Clinic were helpful mentors in cancer biology and receptor signaling during AK’s postdoctoral fellowship We also thank our Linfield students