The calcitonin gene-related peptide family (eBook)

Foreword 5
Contents 7
1 Molecular and Functional Evolution of the Adrenomedullin Family in Vertebrates: What Do Fish Studies Tell Us? 9
1.1 Introduction 10
1.1.1 Body Fluid Regulation in Tetrapods 11
1.1.2 Body Fluid Regulation in Fish 12
1.1.3 Difference in Gravitational Influence on Fish and Tetrapod 13
1.2 Identification of a New AM (Sub)Family 13
1.2.1 AM Peptides in Teleost Fish 14
1.2.2 AM Peptides in Tetrapods 14
1.3 Evolutionary History of the CGRP Family 16
1.3.1 Diversification of CGRP Peptides in Mammals 16
1.3.2 Diversification of CGRP Peptides in Teleost Fish 18
1.3.3 Ancient Molecule of the CGRP Family 20
1.4 Receptors for the CGRP Family Peptides 21
1.5 Biological Actions of the AM Family 22
1.5.1 Biological Actions in Mammals 22
1.5.2 Biological Actions in Teleost Fish 23
1.6 Conclusions and Future Perspectives 24
2 Ligand Binding and Activation of the CGRP Receptor 30
2.1 Introduction 31
2.2 The Structure of the CGRP Receptor Complex 33
2.2.1 The Structure of CGRP 33
2.2.2 The Structure of CLR 34
2.2.2.1 The Extracellular N-Terminus 34
2.2.2.2 The Transmembrane Bundle 35
2.2.2.3 The Putative ‘8th Helix’ 36
2.2.3 The Structure of RAMP1 36
2.2.4 The Structure of RCP 37
2.2.5 The Stoichiometry of the CGRP Receptor 38
2.3 Critical Sites of Contact within the CGRP Receptor Complex 39
2.3.1 RAMP1-CLR Interactions 39
2.3.2 Interactions Between CGRP and CLR 39
2.3.2.1 Putative Interaction Sites in the N-Domain 39
2.3.2.2 Putative Sites in the J-Domain 40
2.3.3 RAMP1 Facilitates CGRP Binding 41
2.4 The Activation Mechanism of the CGRP Receptor 41
2.4.1 Global Activation Mechanism 41
2.4.2 The Role of P3431 and TM6 in CLR 42
2.4.3 The Role of TM-2 and 3 42
2.4.4 The Intracellular Loops 42
2.5 Conclusions and Future Perspectives 44
3 Understanding Amylin Receptors 48
3.1 Amylin and Related Peptides 49
3.2 Amylin Receptors 51
3.2.1 Discovery 51
3.2.2 Molecular Identity of Amylin Receptors 51
3.2.3 Receptor Activity Modifying Proteins 52
3.2.4 Calcitonin Family GPCRs 53
3.2.5 Amylin Receptor Pharmacology 55
3.2.5.1 Agonist Pharmacology 56
3.2.5.2 Antagonist Pharmacology 57
3.2.6 Structure–Function 58
3.2.7 Second Messenger Activation 59
3.2.8 Regulation of Receptors 60
3.2.9 Summary and Future Perspectives 61
4 The CGRP-Receptor Component Protein: A Regulator for CLR Signaling 65
4.1 Introduction 66
4.2 CLR Accessory Proteins 67
4.3 Role of RCP in Cell Culture 68
4.4 Role for RCP In Vivo 68
4.4.1 RCP in Uterus 69
4.4.2 RCP in CNS 70
4.4.3 RCP in Vasculature 71
4.5 RCP Mechanism 72
4.5.1 Drosophila RCP 72
4.5.2 Yeast RCP 74
4.6 Perspective and Future Directions 74
5 The Calcitonin Peptide Family: What Can We Learn from Receptor Knock Out and Transgenic Mice 80
5.1 Introduction 81
5.2 Peptides of the Calcitonin Family 81
5.3 Receptors of the CT Peptide Family 82
5.4 Models of Genetically Modified Mice 83
5.4.1 CTR Knock Out Mice 84
5.4.2 CLR and RAMP Knock Out Mice 84
5.4.3 CLR and RAMP Transgenic Mice 88
5.5 Conclusions and Future Perspectives 89
6 Gene Targeted Mouse Models of Adrenomedullin Signaling 92
6.1 Introduction 93
6.2 Conserved Phenotypes 94
6.2.1 Expression of AM, Calcrl and RAMP2 Are Required for Survival 94
6.2.2 AM Signaling Is Necessary for Lymphatic Vascular Development 95
6.2.3 Genetic Reduction of AM Signaling Components Does Not Impact on Basal or Stress-Induced Blood Pressures 96
6.2.4 Maternal Haploinsufficiecncy for AM Signaling Compromises Fertility, Placentation, and Fetal Growth 96
6.3 Divergent Phenotypes 97
6.4 Perspective and Future Directions 98
7 Genetic Regulation of CGRP and Its Actions 101
7.1 CGRP Promoter 102
7.1.1 Proximal Elements 103
7.1.2 Distal Elements 104
7.2 Signal Transduction Regulating CGRP Gene Expression 105
7.2.1 MAPK: Activator of CGRP Gene Expression 106
7.2.2 PKA and PKC-Mediated CGRP Gene Expression 106
7.2.3 Autoregulation of CGRP 107
7.2.4 Activin: Ally of NGF in CGRP Gene Activation 107
7.2.5 Down-Regulation of the CGRP Gene 108
7.3 Pathology Involved in Aberrant CGRP Gene Regulation 109
7.3.1 DNA Methylation of the CGRP Gene in Cancer 109
7.3.2 Tissue-Wide CGRP Gene Expression in Sepsis 109
7.4 CGRP Action through RAMP1 110
7.4.1 Possible Up-Regulation of the CGRP Gene in Migraine 110
7.4.2 RAMP1 as a Limiting Factor of CGRP Action 111
7.4.3 RAMP1 Transgenic Mouse 111
7.4.4 Behavioral Features of RAMP1 Transgenic Mouse 113
7.5 Conclusions and Future Perspectives 113
8 Vascular Actions of CGRP and Adrenomedullin: Mechanisms and Potential Contribution to Inflammation in the Cutaneous Microvascu 119
8.1 Introduction 120
8.1.1 Receptors 121
8.1.2 Vascular Mechanisms 121
8.2 Role of CGRP and Adrenomedullin in the Microcirculation of the Skin and Related Beds 123
8.2.1 Vasodilator Mechanisms 124
8.2.2 Role in Inflammation – Oedema Formation 126
8.2.3 Role in Inflammation – Cell Accumulation 128
8.2.4 Role in Inflammatory Hyperalgesia 129
8.3 Conclusions and Future Perspectives 130
9 Insights into the Function of Intermedin/Adrenomedullin 2 135
9.1 Human Calcitonin/CGRP Gene Family Includes Five Family Members 136
9.2 Calcitonin/CGRP/Amylin/Adrenomedullin/Intermedin Family Hormones Are Important for the Regulation of Diverse Physiologic 137
9.2.1 Calcitonin, CGRP, and Amylin Subfamily 137
9.2.2 Adrenomedullin and Intermedin Subfamily 138
9.3 Physiological Actions of Calcitonin/CGRP/Amylin/Adrenomedullin/Intermedin Family Peptides Are Mediated via Two Class B G 139
9.4 Intermedin Plays Important Regulatory Roles in the Cardiovascular and Endocrine Systems 141
9.5 Effects of Intermedin on the Cardiovascular System 141
9.5.1 General Circulation 141
9.5.2 Uterus Vasculature 142
9.6 Effects of Intermedin on Neuroendocrine and Endocrine Systems 143
9.6.1 Neuroendocrine System 143
9.6.2 Endocrine System – Paracrine Regulation of Pituitary Prolactin Release by Intermedin 143
9.6.3 Endocrine System – Pituitary Intermedin Expression Is Regulated by Estrogens 144
9.7 Conclusions and Future Perspectives 147
10 CGRP and Adrenomedullin as Pain-Related Peptides 154
10.1 Introduction 155
10.2 CGRP as a Pain-Related Peptide 156
10.2.1 Anatomical Distribution of CGRP in Nociception-Related Areas 156
10.2.2 Role of CGRP in Nociception 157
10.2.3 Role of CGRP in Inflammatory Pain 161
10.2.4 CGRP in Migraine Pain 162
10.2.5 Role of CGRP in Neuropathic Pain 163
10.2.6 Role of CGRP in the Development of Morphine Tolerance and Physical Dependence 164
10.3 Adrenomedullin as a Pain-Related Peptide 165
10.3.1 Role of AM in Nociception 165
10.3.2 Role of AM in Inflammatory Pain 167
10.3.3 Role of AM in Morphine Tolerance and Physical Dependence 168
10.4 Concluding Remarks and Future Perspectives 169
11 Amylinergic Control of Ingestive Behaviour 175
11.1 Introduction 176
11.2 Physiological Relevance of Amylin as Satiation Signal 176
11.3 Mechanisms of Amylin Action 177
11.4 The Amylin-Mediated Fos Response in the AP Is Modulated by Nutrients 178
11.5 Hypothalamic Involvement in Amylin Action 178
11.6 Interactions of Amylin with CCK and Peptide YY (PYY) 179
11.7 Interactions of Amylin with Leptin and Insulin 179
11.8 Amylin as an Adiposity Signal 180
11.9 Amylin’s Effect on Energy Metabolism 182
11.10 Amylin and Obesity Therapy in Humans 182
11.11 Summary, Conclusions and Future Perspectives 183
12 CGRP Receptor Antagonists for Migraine: Challenges and Promises 187
12.1 Introduction 188
12.2 CGRP and Migraine 189
12.3 The Challenges of Targeting the CGRP Receptor 189
12.3.1 Species Selectivity of Small Molecule Antagonists 190
12.3.2 Adrenomedullin Receptor Selectivity 192
12.3.3 Receptor Determinants of Small Molecule Antagonist Affinity 193
12.4 Clinically Translatable Pharmacodynamic Assay 195
12.5 CGRP Receptor Antagonists as a Novel Antimigraine Therapy 195
12.6 Conclusions 196
13 Calcitonin Receptor Expression in Embryonic, Foetal and Adult Tissues: Developmental and Pathophysiological Implications 200
13.1 Introduction 202
13.1.1 The Original Assignment of the Endocrine Function of the Calcitonin (CT)/Receptor (CTR) System 202
13.1.2 A Brief Overview of the Pharmacology of CTR, a G-Protein Coupled Receptor (GPCR) 202
13.1.3 CTR and the Formation of Heterodimeric Complexes 203
13.1.4 The Control of Expression of CTR mRNA 204
13.2 Widespread Expression in Adult Tissues 205
13.3 Studies with Anti-CTR Antibodies 205
13.3.1 Anti-CTR Antibodies Used in Early Studies 205
13.3.2 The Development of High Affinity Anti-CTR Antibodies 205
13.3.3 Immunohistochemistry and Immuno-Fluorescence with High Affinity Anti-CTR Antibodies 209
13.3.4 Verification of Antibodies IHC Versus ISH, WB and FACS 210
13.4 CTR Expression During Embryonic and Foetal Development 210
13.4.1 CT/CTR in Development of the Early Blastocyst and Gastrula 210
13.4.2 CTR-b Gal Transgenic Mouse Models 210
13.4.3 CTR-Positive Precursor Cells That Migrate During Foetal Development 211
13.4.4 Co-expression of CTR with the Proto-Oncogene RET in the Gut 213
13.4.5 CTR-Positive Structures in the Developing Thyroid 213
13.4.6 CTR Expression in the Developing and Adult Skeletal Muscle 214
13.4.7 CTR Expression in Postnatal Rodent Developing Kidney (Transient Up-Regulation) 214
13.5 The Expression of CTR by Precursors and Progeny of the Haematopoietic Lineage 215
13.5.1 T Lymphocytes 216
13.5.2 CTR expression and haematopoietic lineages 216
13.6 Wound Healing, a Mouse Model 217
13.7 Cardiovascular Disease (CVD) 219
13.7.1 Rabbit Model of Atherosclerosis 219
13.7.2 More Advanced Human CVD: CTR Expression in the Media and Adventitia, and Calcification 219
13.8 Tumourogenesis 221
13.8.1 CTR Expression in Leukaemia 221
13.8.2 The Expression of the Proto-Oncogene RET in Normal BM and Leukaemia 222
13.9 Possible Cellular Mechanisms Involving CTR 225
13.9.1 Retardation of the Cell Cycle 225
13.9.2 Migration and Recruitment of Precursor Cells and/or Progeny 225
13.9.3 Promotion of Differentiation, for Instance Progeny of the Haematopoietic Lineage 225
13.10 The Micro-environment and CTR-Positive Cell Types 226
13.10.1 What are the Implications for the Co-expression of CTR and RET? 226
13.11 Conclusions and Future Perspectives 227
14 Conclusions and Future Perspectives 235