Extracellular and Intracellular Signaling

Extracellular and Intracellular
Signaling......Page 4
Preface......Page 6
Contents......Page 8
1.1.1 Linear Model of Drug Receptor Interactions......Page 16
1.1.2 Matrix Model of Drug Receptor Interactions......Page 17
1.2 Experimental Approaches to Disease Treatment......Page 18
1.3 Adipokines and Disease Causation......Page 19
1.4 Questions in Disease Treatment......Page 21
1.5 Toxic Lifestyles and Disease Treatment......Page 22
References......Page 24
2.1 Introduction......Page 25
2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion......Page 26
2.3 Feedback between FA and the Adipocyte......Page 29
2.4 Autocrine Effects of Leptin and Adiponectin
in Adipocytes......Page 30
2.5 Potential Effects of PPARa Deficiency
on Autocrine Signaling in Adipose Tissue......Page 32
2.6 Metabolic Programming of Autocrine Signaling
in Adipose Tissue......Page 34
2.7 Autocrine Effects on Adipose Tissue Could
Modulate the Operation of the Adipocyte
Circadian Clock......Page 35
2.8 Cell Heterogeneity in the Pancreatic Islet......Page 36
2.9 Autocrine Effects of Insulin on the Pancreatic
β Cell......Page 37
2.10 Is Early Life Programming of Insulin Resistance
by Altered Insulin Signaling Accompanied by an
Abnormal Autocrine Effect of Insulin on the
Pancreatic β Cell?......Page 40
2.11 Effects of FA on the Pancreatic β cell......Page 41
2.12 Effects of Leptin and Adiponectin on the
Pancreatic β Cell......Page 42
2.14 Is Programmed Obesity Associated with β-cell
Inflammation?......Page 44
2.15 Other Adipose-derived Factors that Could
Contribute to the Adipoinsular Axis......Page 45
References......Page 47
3.1 Leptin......Page 59
3.3.1 The JAK2-STATs Routes......Page 60
3.3.2 ERK1/2......Page 63
3.3.4 AMPK......Page 64
3.4 Leptin Receptor Interactions......Page 65
3.4.3 Diacylglycerol Kinase Zeta......Page 66
References......Page 67
4.1 Introduction......Page 72
4.3 Expression of Leptin Receptors in Cardiovascular
Tissues......Page 73
4.5 Cardiomyocyte Hypertrophic Effects of Leptin......Page 74
4.6.1 JAK-STAT Pathway Activation......Page 76
4.6.2 Mitogen Activated Protein Kinase Stimulation......Page 77
4.7 Adiponectin......Page 78
4.7.2 Adiponectin and Experimental Cardiac Hypertrophy......Page 79
4.7.3 Cell Signaling Mechanisms Underlying Cardioprotective
and Antihypertrophic Effects of Adiponectin......Page 80
4.8 Resistin......Page 81
4.9 Apelin......Page 82
4.10 Visfatin......Page 83
4.11 Other Novel Adipokines......Page 84
References......Page 85
5.1 Basic Protein Synthesis......Page 92
5.2.1 Hormones......Page 94
5.2.1.2 Mechanisms of Action: TH (T3)......Page 95
5.2.1.4 Mechanisms of Action: Epinephrine......Page 96
5.2.2 Local Factors (Autocrine/Paracrine)......Page 97
5.2.2.1 Mechanisms of Action: Insulin/IGF Spliceoforms......Page 98
5.2.2.2 Mechanisms of Action: Fibroblast Growth Factor (FGF)......Page 99
5.2.2.4 Mechanisms of Action: Cytokines......Page 100
5.2.2.6 Mechanisms of Action: Acetylcholine (ACh)/Ca²+......Page 101
5.2.2.8 Mechanisms of Action: Amino Acids (AA)......Page 102
5.3 Regulation of Muscle Proteostasis in Humans......Page 103
5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man......Page 104
5.3.1.1 AA as Extracellular–Intracellular Signals......Page 105
5.3.2 Muscular Activity (i.e. Exercise) as a Regulator
of Muscle Proteostasis......Page 107
5.3.2.1 Extracellular–Intracellular Signaling and Muscular
Activity......Page 108
5.4 Conditions Associated with Alterations in Muscle
Proteostasis in Humans......Page 110
5.4.1 Effects of Aging on Muscle Proteostasis......Page 111
5.4.2 Disuse Atrophy......Page 112
5.4.3 Sepsis......Page 114
5.4.4 Burns......Page 115
5.4.5 Cancer Cachexia......Page 116
References......Page 117
6.1 Introduction......Page 120
6.3 Cadherins......Page 121
6.4 Gap Junctions......Page 122
6.5 Contact Normalization and Tumor Suppressors......Page 123
6.6 Contact Normalization and Tumor Promoters......Page 124
References......Page 125
7.1 Introduction......Page 131
7.2 Background on Migraine Headache......Page 132
7.3 Migraine and Neuropathic Pain......Page 134
7.4 Role of Astrocytes in Pain......Page 136
7.5 Adipokines and Related Extracellular Signalling......Page 137
Acknowledgements......Page 140
References......Page 141
8.1 Alzheimer’s Disease......Page 145
8.1.1 β-Amyloid and Tau......Page 146
8.1.2 Target for AD Therapy......Page 148
8.2.1 Impaired Glucose Metabolism......Page 149
8.2.2 Lipid Disorders......Page 150
8.3 Adipokines......Page 151
8.3.1 Leptin......Page 152
8.3.3 Resistin......Page 154
8.3.5 Plasminogen Activator Inhibitor......Page 155
8.3.7 Transforming Growth Factor-β1......Page 156
References......Page 157
9.1.1.1 Morphology......Page 164
9.1.1.2 Astrocyte Functions......Page 165
9.1.2.1 Reactive Astrocytosis......Page 166
9.1.2.3 Alzheimer Type II Astrocytosis......Page 169
9.2.1 Oxidative/Nitrosative Stress (ONS)......Page 170
9.2.4 Mitogen-activated Protein Kinases (MAPKs)......Page 171
9.2.5 Signal Transducer and Activator
of Transcription 3 (STAT3)......Page 172
9.3 Signaling Systems in Astrocyte Swelling......Page 173
9.3.2 Cytokines......Page 174
9.3.5 Protein Kinase G (PKG)......Page 175
9.3.8 Nuclear Factor Kappa B (NF-κB)......Page 176
9.3.10 Ion Channels/Transporters/Exchangers......Page 177
9.4 Conclusions and Perspectives......Page 178
References......Page 180
10.1 Adipokines, Toxic Lipids and the Aging Brain......Page 190
10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids......Page 191
10.1.3 Endocannabinoids, Ceramide and Amyloidb......Page 192
10.2.1 Visfatin and the Blood-Brain Barrier......Page 193
10.3 Oxygen Radicals, Hydrogen Peroxide
and Cell Death......Page 194
10.4 Gene Transcription and DNA Damage......Page 198
References......Page 199
11.1 Introduction......Page 203
11.2.1 Types of Signaling......Page 205
11.2.2 Membrane Proteins in Signaling......Page 206
11.3 G Protein-Coupled Receptors......Page 207
11.3.1 Structure of GPCRs......Page 208
11.3.1.1 Structure Determination......Page 210
11.3.1.2 Structural Diversity of Current GPCR Structures......Page 211
11.3.1.3 Prediction of GPCR Structure and Ligand Binding......Page 214
11.3.2.1 Multi-Conformational View of GPCRs......Page 218
11.3.2.2 Ligand or Mutation Stabilized Ensemble
of GPCR Conformations......Page 219
11.3.2.3 Intracellular Signal Diversification and
GPCR Regulation......Page 224
11.3.2.4 GPCR Dimers and Interaction with Other Proteins......Page 231
11.3.3 Functional Control of GPCRs by Ligands......Page 232
11.3.3.1 Biased Agonism......Page 233
11.3.3.2 Allosteric Ligands and Signal Modulation......Page 234
11.3.4 Challenges in GPCR Targeted Drug Design......Page 236
11.4 Summary and Looking Ahead......Page 238
Acknowledgements......Page 239
References......Page 240
12.1 Introduction......Page 245
12.2 Overview of the Inflammatory Cascade......Page 246
12.3 Overview of NF-κB......Page 247
12.4 PPARγ and LXRs Regulate NF-κB......Page 248
12.5.1 Anthocyanins......Page 250
12.5.2 Gallates......Page 251
12.5.4 Isoflavones......Page 252
12.5.5 Piperine......Page 253
12.5.7 Curcumin......Page 254
12.5.8 Guggulsterone......Page 255
12.6.2 Dehydroabietic Acid......Page 256
12.7.1 Stigmasterol......Page 257
12.8 Conclusion......Page 258
References......Page 259
13.1 Introduction......Page 262
13.2 Selective Dopaminergic Neuronal Death......Page 263
13.3.1.1 Response to Oxidative and Nitrosative Stress......Page 269
13.3.1.2 Response to Altered Proteostasis......Page 273
13.3.1.3 Response to Glutamate......Page 275
13.3.2.1 Ca²+......Page 276
13.3.3.1 Mitogen Activated Protein Kinases (MAPK) Pathway......Page 278
13.3.3.3 NFkB Signaling Cascade......Page 280
13.3.4.1 AMP-Activated Protein Kinase (AMPK)......Page 281
13.3.5 Effector Pathways and Final Effects......Page 282
13.3.5.2 Dopamine Metabolism......Page 283
13.3.5.4 Autophagy......Page 284
13.4 Conclusions......Page 285
References......Page 286
Subject Index......Page 298