Cellular Peptide Hormone Synthesis and Secretory Pathways (eBook)

Preface 5
Maturation of Secretory Granules 9
1 Introduction 9
2 Formation of ISGs at the TGN 11
2.1 Aggregation 11
2.2 Sorting Motifs and Cargo–Membrane Interaction 12
3 Transport of Maturing ISGs 14
4 Mechanistic Insights into ISG Maturation 15
4.1 Homotypic Fusion 16
4.2 Sorting by Retention 16
4.3 Acidification 18
5 Maturation into Vesicle Pools 19
6 Summary 22
References 22
Chromogranins A and B and Secretogranin II as Prohormones for Regulatory Peptides from the Diffuse Neuroendocrine System 29
1 Introduction 29
2 Granins and Granin-Derived Peptides 30
2.1 The Prohormone Concept 30
2.2 CgA 31
2.3 CgB 32
2.4 SgII 33
3 Functional Aspects 33
4 Granin Peptides and Targets 36
4.1 Antimicrobial Potencies and Innate Immunity 36
4.2 Inflammatory Conditions 37
4.3 Other Cardiovascular Functions 40
4.4 CgA Peptides as Modulators of Calcium and Carbohydrate Homeostasis 43
5 Towards a Unifying Concept for Extracellular Functions of CgA, CgB, and SgII 44
References 46
Cell-Specific Precursor Processing 53
1 Introduction 53
2 Examples of Cell-Specific Prohormone Processing 55
3 Significance of the Cell-Specific Processing in Disease 62
4 Processing-Independent Analysis 64
5 Summary 65
References 66
ACTH: Cellular Peptide Hormone Synthesis and Secretory Pathways 71
1 Introduction 71
2 POMC Synthesis and Its Regulation 73
3 POMC Processing: The Peptides Produced and the Cleavage Pathway 74
3.1 Processing of POMC to ACTH 74
3.2 Processing of ACTH by PC2 75
3.3 Post-Translational Processing to Produce aMSH 75
4 The Secretion of Processed POMC Peptides 76
5 Incomplete Processing of POMC: When, How and Why? 84
6 Conclusion 87
References 88
Neurotensin and Neuromedin N Are Differentially Processed from a Common Precursor by Prohormone Convertases in Tissues and Cell Lines 93
1 Introduction 93
2 The Neurotensin Precursor Also Contains Neuromedin N 95
3 Pro-NT/NN Is Differentially Processed in Tissues and Cell Lines 95
3.1 Differential Processing in the Brain, Gut and Adrenals 96
3.2 Processing in Cell Lines 96
4 Pro-NT/NN Processing by Prohormone Convertases 98
5 Involvement of PCs in Pro-NT/NN Processing in Tissues and Cell Lines 99
6 Carboxypeptidase E and Dibasic Removal 100
7 Physio-Pathological Implications 101
8 Conclusions 102
References 102
Biosynthesis of Cardiac Natriuretic Peptides 105
1 Introduction 105
2 Peptide Nomenclature and Biosynthesis 107
3 The Pre-Translational Phase of B-Type Natriuretic Peptide Gene Expression 108
4 The Primary Structure of ProBNP 110
5 The Post-Translational Phase of B-Type Natriuretic Peptide Gene Expression 111
5.1 Disulphide Bond Formation 111
5.2 Glycosylation 112
5.3 Endoproteolysis 114
5.4 Exoproteolysis 115
6 Cellular Storage and Secretion 116
7 ProBNP-Derived Peptides in Plasma 118
8 Biosynthesis and Assay Calibration 119
9 Inefficient Prohormone Maturation in Heart Failure 120
10 Concluding Remarks 121
References 122
Glucagon and Glucagon-Like Peptides 1 and 2 129
1 Introduction 129
2 Proglucagon Gene Expression 132
3 Posttranslational Processing and Chemical Structures 134
4 Localization of Proglucagon Expression 136
5 Postsecretory Fate of Proglucagon-Derived Peptides 137
References 139
Somatostatin and Somatostatin Receptors 144
1 Introduction 144
2 Somatostatin Processing 146
3 Somatostatin Distribution 147
4 Somatostatin Physiology 148
5 Somatostatin Regulation 150
6 A New Member in the Somatostatin Family? 151
7 Somatostatin Receptors 152
8 Development of Somatostatin Receptor Ligands 154
9 Somatostatin Receptor Localization 156
10 Regulation of Somatostatin Receptor Genes 158
11 Somatostatin Receptor Signaling 158
12 Relevance of SSTRs in Cancer 161
13 Agonist-Regulation of Somatostatin Receptors 164
14 Dimerization of SSTRs 168
15 Conclusions 172
References 173
Ghrelin: From Gene to Physiological Function 192
1 Introduction 192
2 Genomic Structure of Ghrelin 193
3 Promoter and Expression of Ghrelin Gene 195
4 Processing of Ghrelin Precursor to Des-Acyl Ghrelin 195
5 Acyl-Modification of Ghrelin by Ghrelin O- Acyltransferase ( GOAT) 197
6 Substrate Specificity of GOAT 198
7 n-Octanoyl Ghrelin Is the Major Form of Gastric Ghrelin 199
8 Des-Acyl Ghrelin 199
9 Multiple Forms of Ghrelin in Human Stomach 200
10 Molecular Forms of Ghrelin in Jejunum, Pancreas and Hypothalamus 200
11 Obestatin, a Ghrelin Precursor-Derived Peptide? 200
12 Regulation of Ghrelin Secretion 201
13 Abnormal Ghrelin Secretion in Prader–Willi Syndrome 203
14 Pathway of Ghrelin Signal: From Peripheral Tissues to Central Nervous System 203
15 Ghrelin Stimulates Appetite in the Hypothalamus 204
16 Molecular Mechanism of Appetite Stimulation by Ghrelin 206
17 Epilogue 207
References 208
Posttranslational Processing of Progastrin 213
1 Introduction 214
2 The Structure of Progastrin 215
3 Intracellular Transport and Posttranslational Processing Events 216
4 Processing Characteristics of Progastrin 218
5 A Model for the Biosynthesis of Progastrin 222
6 Conclusions 223
References 223
VIP and PACAP 227
1 Introduction 227
2 Discovery of VIP 228
3 Structure of the VIP Precursor 228
4 Co-Existence and Co-Secretion of VIP and PHI 229
5 Glycine-Extended VIP 230
6 Expression of Other VIP Precursor-Derived Peptides 231
7 PreproVIP-Derived Peptides in Patients with VIP- Producing Tumours 233
8 Discovery of PACAP 233
9 Structure of PACAP Precursor 234
10 Expression of PACAP Precursor-Derived Peptides 235
11 Conclusion 237
References 237
Index 241