Membrane Receptors, Channels and Transporters in Pulmonary Circulation (eBook)

Advances in Experimental Medicine and Biology 1
Membrane Receptors, Channels and Transporters in Pulmonary Circulation 2
Contents 12
Preface 4
Ion Channels in the Pulmonary Vasculature: Basics and New Findings 16
The Role of Ion Channels in Hypoxic Pulmonary Vasoconstriction 17
1 Introduction 17
2 Oxygen Sensing and Ion Channels in the Carotid Body 18
3 Hypoxic Pulmonary Vasoconstriction 19
4 K+ Channels and HPV 19
6 Intracellular Calcium Release and HPV 21
7 Store-Operated Calcium Channels 22
8 Depolarization and Calcium Release 22
9 TRPCs and HPV 24
10 Normoxic Contraction of the Ductus Arteriosus 24
11 Store-Operated Channels and Normoxic Contraction of the DA 25
12 Conclusion 26
References 26
Two-Pore Domain K+ Channels and Their Role in Chemoreception 29
1 Chemosensing and Background/Leak K+ Channels 29
2 Two-Pore-Domain Potassium Channels 30
2.1 Structure 30
2.2 Classification and Nomenclature 31
2.3 Biophysical Characteristics 32
2.4 Regulation and Pharmacology of K2P Channels 32
2.4.1 Classical K+ Channel Inhibitors 32
2.4.2 Extracellular pH 32
2.4.3 Intracellular pH 33
2.4.4 Temperature 33
2.4.5 Polyunsaturated Fatty Acids and Lysophospholipids 33
2.4.6 Membrane Stretch and Stress 33
2.4.7 Gaseous General Anaesthetics 34
2.4.8 Other Pharmacology 34
2.5 Identifying Endogenous Channels 34
3 Endogenous Background Potassium Channels and Their Role in Chemoreception 35
3.1 Central Chemoreceptors and Acid or CO2 Sensing 35
3.2 Peripheral Chemoreceptors: Acid and Oxygen Sensing 36
3.3 Adrenal Gland: Potassium Sensing 37
3.4 Hypothalamus: Glucose Sensing 38
4 Summary 39
References 39
Intricate Interaction Between Store-Operated Calcium Entry and Calcium-Activated Chloride Channels in Pulmonary Artery Smooth 45
1 Introduction 46
2 Materials and Methods 48
2.1 Isolation of Pulmonary Artery Myocytes 48
2.2 Contractile Studies 49
2.3 Patch Clamp Electrophysiology and Experimental Protocols 49
2.4 Intracellular Ca2+ Concentration Measurements 50
2.5 Solutions and Reagents 50
2.6 Reverse-Transcriptase Polymerase Chain Reaction Experiments 52
2.7 Statistical Analysis 53
3 Results 53
3.1 Demonstration of Store-Operated Ca2+ Entry 53
3.2 SOCE Activates Ca2+-Activated Cl.– Conductance 54
3.3 Voltage Dependence of SOCE and Impact on ICl(Ca) 58
3.4 Molecular Candidates for the Store-Operated Calcium Entry Pathway 60
3.5 Molecular Candidates for the Calcium-Activated Chloride Channel 60
4 Discussion 62
4.1 Detection of SOCE-Induced Contraction in the Rabbit Pulmonary Arterial Vasculature 62
4.2 SOCE Activates Ca2+-Activated Cl– Current 63
4.3 Nature of the Ca2+ Entry Pathway Stimulating ClCa Channels 64
5 Conclusion 66
References 67
The Role of Intracellular Ion Channels in Regulating Cytoplasmic Calcium in Pulmonary Arterial Smooth Muscle: Which Store an 70
1 Introduction 70
2 Hypoxic Pulmonary Vasoconstriction 71
2.1 Regulation by Hypoxia of Calcium Mobilisation from Sarcoplasmic Reticulum Calcium Stores in Pulmonary Artery Smooth Muscl 71
2.2 ADP-Ribosyl Cyclase and cADPR Hydrolase Activities Are Differentially Distributed in Pulmonary Versus Systemic Artery Smo 73
2.3 The cADPR Antagonist 8-Bromo-cADPR Identifies cADPR-Independent and cADPR-Dependent Phases of Smooth Muscle SR Ca2+Re 74
2.4 8-Bromo-cADPR Blocks Phase 2 of HPV in an All-or-None Manner 74
3 NAADP Induces Global Ca2+ Waves and Smooth Muscle Contraction in an All-or-None Manner 75
3.1 NAADP Triggers Ca2+Bursts from Lysosome-Related Acidic Stores that Are Amplified by Ca2+-induced Ca2+ release from 75
3.2 Possible Role of cADPR in the Modulation of NAADP-Dependent Ca2+Signalling 77
4 Lysosome-Sarcoplasmic Reticulum Junctions Form a Trigger Zone for Ca2+ Signalling by NAADP 78
4.1 Lysosomes Co-localise with a Sub-population of RyRs 78
4.2 Lysosomes Co-localise with RyR Sub-type 3 to Form a Trigger Zone for Ca2+Signalling by NAADP in Pulmonary Arterial Smoo 79
4.3 Why Might RyR3 Be Targeted to Lysosome–SR Junctions? 80
4.4 How May Ca2+Signals Propagate Away from Lysosome–SR Junctions to the Wider Cell If RyR3 Is Targeted to the Perinuclear 81
4.5 RyR1 Is may be the predominant RyR subtype in the Sub-plasmalemmal Region of the Cell 82
5 Discrete SR Compartments Underpin Ca2+-Dependent Vasodilation and Vasoconstriction 82
5.1 Cyclopiazonic Acid and 8-Bromo-cADPR Reveal Two Functionally Segregated SR Ca2+Stores 82
5.2 SERCA2a and SERCA2b Serve Discrete SR Compartments in Pulmonary Arterial Smooth Muscle 84
5.3 Possible Role of cADPR-Independent and cADPR-Dependent Phases of SR Ca2+Release by Hypoxia 85
6 Summary 85
References 87
Ca2+ Oscillations Regulate Contraction Of Intrapulmonary Smooth Muscle Cells 90
1 Introduction 90
2 Lung Slices 91
3 Response of Arterioles to Agonists 93
4 Ca2+ Signaling of Intrapulmonary SMCs 96
4.1 Roles of Ca2+ Influx and Internal Ca2+ Release 99
4.2 Effect of KCl on Arteriole SMC Physiology 100
4.3 Ca2+ Sparks: A Relaxation Mechanism in Pulmonary SMCs? 101
4.4 The Role of Ryanodine Receptors 102
5 Frequency-Modulation as Method for Contraction Regulation 102
6 The Influence of Ca2+ Sensitivity on Contraction 103
6.1 A Unique Nondestructive Technique for Ca2+ Permeabilization 104
6.2 Agonist-Induced Increases in Ca2+ Sensitivity 104
7 Relaxation Mechanisms of SMCs 106
8 Conclusions 107
References 108
TRP Channels in the Pulmonary Vasculature: Basics and New Findings 110
Introduction to TRP Channels: Structure, Function, and Regulation 111
1 Introduction 111
2 TRP Gene Expression 112
3 TRP Protein and Channel Function 112
4 TRP Channel Regulation 112
5 Summary of Mammalian TRPs (Fig. 6.1) 113
5.1 TRPC 113
5.2 TRPV 113
5.3 TRPM 115
5.4 TRPA 116
5.5 TRPP 117
5.6 TRPML 117
6 Conclusion 117
References 117
Physiological Functions of Transient Receptor Potential Channels in Pulmonary Arterial Smooth Muscle Cells 121
1 Introduction 122
2 Expression of TRP Channels in Pulmonary Artery Smooth Muscle Cells 122
3 Physiological Functions of TRP Channels in PASMCs 124
3.1 Store-Operated and Receptor-Operated Ca2+ Entry 124
3.2 Agonist-Induced Pulmonary Vasoconstriction 126
3.3 Hypoxic Pulmonary Vasoconstriction 127
3.4 PASMC Growth and Proliferation 128
3.5 Pulmonary Arterial Hypertension 129
3.5.1 Chronic Hypoxia-Induced Pulmonary Hypertension 129
3.5.2 Idiopathic Pulmonary Arterial Hypertension 131
4 Conclusion 132
References 132
The Contribution of TRPC1 and STIM1 to Capacitative Ca2+ Entry in Pulmonary Artery 135
1 Introduction 135
2 Molecular Composition and Molecular Signals that Underlie Store-Operated Channels in Vascular Smooth Muscle 137
3 Role of TRPC1 as an Essential Component for Store-Operated Channels in Pulmonary Artery 138
4 STIM1 Mediates Capacitative Ca2+ Entry in Pulmonary Artery Smooth Muscle 140
5 Functional Interaction of TRPC1 and STIM1 in Pulmonary Artery Smooth Muscle 140
6 Summary and Conclusions 143
References 145
Store-Operated Calcium Entry Channels in Pulmonary Endothelium: The Emerging Story of TRPCS and Orai1 148
1 Introduction 148
2 Fidelity of Calcium Signals in Endothelium 149
3 Activation of Store-Operated Calcium Entry Increases Endothelial Cell Permeability 150
4 TRPC Proteins Form the ISOC Channel 153
5 Orai Proteins and Their Relationship to TRPC Channels 157
6 Protein 4.1 Is an Essential Determinant of TRPC1/3/4 Activation 160
7 Summary 161
References 162
TRPM2 Channel Regulates Endothelial Barrier Function 166
1 Introduction 166
2 Role of TRPM2 Channel in Mediating H2O2-Induced Ca2+ and Endothelial Hyperpermeability 168
2.1 TRP Channels in the Regulation of Lung Endothelial Barrier Function 168
2.2 TRPM2 Regulates H2O2-Induced Ca2+ Entry in Endothelial Cells 168
2.3 Role of TRPM2 in Inflammation and Oxidant-Induced Vascular Hyperpermeability 169
3 Role of TRPM2 Channel-Activated Ca2+ Entry in Mediating Neutrophil-Induced Lung Injury 172
3.1 Neutrophil-Induced Ca2+ Entry in Endothelial Cells Involves TRPM2 Channels 172
3.2 Neutrophils Activate Endothelial TRPM2 as an Essential Step in Transendothelial Migration 173
4 PKCa Modulation of TRPM2 Channel Regulates H2O2-Induced Ca2+ Entry and Endothelial Permeability 173
4.1 PKCa Modulation of TRPM2 Regulates H2O2–Ca2+ Entry in Endothelial Cells 173
4.2 TRPM2-Activated Increase in Endothelial Permeability Involves a PKCa 174
4.3 H2O2 Induces PKCa Association with TRPM2-S 174
5 Conclusions and Perspectives 175
References 176
Pathogenic Role of Ion Channels in Pulmonary Vascular Disease 179
A Proposed Mitochondrial–Metabolic Mechanism for Initiation and Maintenance of Pulmonary Arterial Hypertension in Fawn-Hooded 180
1 Introduction 180
2 An Emerging Paradigm: The “Oncologic” View of Pulmonary Artery Hypertension 181
3 Overview of Existing Mechanisms of PAH 181
4 The Fawn-Hooded Rat as a Model for Idiopathic Pulmonary Artery Hypertension 183
5 A Metabolic Axis of Pulmonary Artery Hypertension 183
5.1 Epigenetic Silencing of SOD2 and the Role of H2O2 in PAH 184
5.2 HIF-1a Activation and the “Pseudohypoxic” State in PAH 185
5.3 PDK Activation in PAH and Cancer 186
6 The Vicious Cycle of Metabolic Dysregulation in PAH 188
7 Integrating Other Theories of PAH with the Mitochondrial–Metabolic Model 189
8 Summary 189
References 190
The Role of Classical Transient Receptor Potential Channels in the Regulation of Hypoxic Pulmonary Vasoconstriction 195
1 Introduction 195
2 The Classical Transient Receptor Potential Family of Nonselective Cation Channels 197
2.1 Introduction 197
2.2 Identification and Structural Properties of Mammalian TRP Channels 197
2.3 Characteristics of the TRPC Channel Subfamily 199
2.4 Expression Pattern and Function of TRPC Channels 199
3 Role of the TRPC Channels in Acute Hypoxic Pulmonary Vasoconstriction 200
3.1 Role of Ca2+Channels in Acute HPV 200
3.2 Importance of TRPC6 Channels in Acute HPV 201
3.3 Role of TRPC6 Channels in the Increase of Intracellular Ca2+ Concentration in Acute HPV 203
3.4 Activation of TRPC6 Channels in Acute HPV 204
3.5 Hypothesis of the Mechanism of Acute HPV 204
4 Conclusion 205
References 206
Developmental Regulation of Oxygen Sensing and Ion Channels in the Pulmonary Vasculature 209
1 Introduction 209
2 K+ Channels in the Pulmonary Circulation 210
3 Role of the Calcium-Sensitive K+ Channel in the Perinatal Lung 211
4 Ontogeny of the Pulmonary Vascular K+ Channel and O2 Sensing 212
5 Developmental Regulation of Oxygen-Induced Vasodilation 215
6 Oxygen-Induced Fetal Pulmonary Vasodilation Is Ryanodine Sensitive 216
7 Oxygen Tension Modulates the Expression of Pulmonary Vascular BKCa Channel 218
8 Hypoxia-Inducible Factor 1 Modulates BKCa Expression 218
9 Developmentally Regulated Expression of HIF-1 221
10 Prolyl Hydroxylases PHD2 and PHD3 are Developmentally Regulated 222
11 Asparagyl Hydroxylase FIH-1 and CITED2 are Developmentally Regulated 224
12 Conclusions 224
References 225
Hypoxic Regulation of Ion Channels and Transporters in Pulmonary Vascular Smooth Muscle 229
1 Introduction 229
2 Changes in K+ channels with Chronic Hypoxia 230
3 Effect of Chronic Hypoxia on Ca2+ Channels 231
4 Chronic Hypoxia and PASMC Intracellular pH 234
5 Hypoxia-Inducible Factor 1 235
5.1 HIF-1 and Kv Channels 236
5.2 HIF-1 and [Ca2+]i 237
5.3 HIF-1 and Intracellular pH 239
6 Summary 240
References 241
CLC-3 Chloride Channels in the Pulmonary Vasculature 244
1 Introduction 244
2 Properties of Native VSOACs in PASMCs 245
3 Anion Selectivity of Native VSOACs in PASMCs and sClC-3 Heterologously Expressed in NIH/3T3 Cells 248
4 Do Native VSOACs in PASMCs and Heterologously Expressed sClC-3 Behave as Chloride/Proton Antiporters? 250
5 Summary and Conclusions 252
References 253
Receptors and Signaling Cascades in Pulmonary Arterial Hypertension 255
Cross Talk Between Smad, MAPK, and Actin in the Etiology of Pulmonary Arterial Hypertension 270
1 Introduction 270
2 BMPR2 Signaling Pathways 271
2.1 Smad 272
2.2 Mapk 272
2.3 Actin Organization 273
2.4 SRC and NFkB 273
3 In Vivo Consequences of BMPR2 Mutation 274
3.1 Smad 274
3.2 Actin Organization 275
3.3 Mapk 275
3.4 Summary 276
4 The BMP Pathway in Acute Inflammation 276
5 Context and Conclusions 277
5.1 Animal Models 278
5.2 Risk Factors and Modifiers 278
5.3 End-Stage Human Disease 279
5.4 Conclusions 280
References 281
Notch Signaling in Pulmonary Hypertension 284
1 Introduction 284
2 Overview of Notch Signaling 285
3 Notch3 Regulates Specification of Arterial Smooth Muscle Cells 288
4 Studies Supporting a Role of Notch3 in Vascular Smooth Muscle Cell Proliferation and Dedifferentiation 288
5 Notch3 Is a Marker for PAH and PAH Disease Severity 290
6 Cellular Localization of Notch3 and Hes5 to Vascular Smooth Muscle Cells in the Lung 292
7 Notch3 Increases Proliferation in Pulmonary Arteriolar Smooth Muscle Cells 293
8 Increased Proliferation Rate of Human Pulmonary Arteriolar Smooth Muscle Cells from PAH Versus Normal Lungs Is Dependent on 293
9 Notch3–/– Mice Are Resistant to the Development of Pulmonary Hypertension 295
10 In Vivo Inhibition of Notch3 Cleavage by the g-Secretase Inhibitor DAPT Reverses Pulmonary Hypertension in Rodents 297
11 Linking Notch Signaling to Other Pathways Implicated in Pulmonary Hypertension 299
12 Conclusions 301
References 302
Rho Kinase-Mediated Vasoconstriction in Pulmonary Hypertension 304
1 Introduction 305
2 RhoA/Rho Kinase-Mediated Smooth Muscle Cell Contraction and Vasoconstriction 305
3 RhoA/Rho Kinase-Mediated Vasoconstriction in Animal Models of Pulmonary Hypertension 307
4 Evidence of Vasoconstriction in Bone Morphogenetic Protein Type II Receptor-Related Mouse Models of Pulmonary Hypertensio 308
5 Evidence of RhoA/Rho Kinase-Mediated Vasoconstriction in Patients with Pulmonary Arterial Hypertension 309
6 Summary 310
References 311
The Serotonin Hypothesis of Pulmonary Hypertension Revisited 314
1 Pulmonary Arterial Hypertension 314
1.1 Serotonin and the Serotonin Hypothesis 315
2 The Serotonin System in the Pulmonary Arterial Circulation 317
2.1 5-HT Receptors 317
2.2 The Serotonin Transporter 318
2.2.1 SERT and Pulmonary Vascular Remodelling and Vasoconstriction 319
2.3 Serotonin Synthesis 320
2.4 Serotonin-Induced Signalling in Pulmonary Arteries 320
3 Dexfenfluramine-Induced PAH 322
4 SERT and BMPR-II 323
5 The Serotonin Hypothesis Revisited 323
References 324
Impaired Vascular Endothelial Growth Factor Signaling in the Pathogenesis of Neonatal Pulmonary Vascular Disease 328
1 Introduction 328
2 VEGF Signaling During Lung Development 329
3 Altered VEGF Signaling in the Pathogenesis of PPHN 331
4 Disruption of VEGF Signaling in the Pathogenesis of BPD 334
5 Summary 337
References 338
Role of Bone Morphogenetic Protein Receptors in the Development of Pulmonary Arterial Hypertension 256
1 Introduction 256
2 The Pathology of PAH 257
3 Genetics of Familial PAH 257
4 Normal BMPR-II Signalling 258
5 Interactions Between MAPK and Smad Signalling 260
6 The Consequences of BMPR2 Mutation for BMP/TGF-b Signalling 260
7 Studies in Cells and Tissues from PAH Patients 262
8 Studies in Transgenic and Knockout Mice 264
9 BMPs as Inhibitors of Tissue Remodelling 265
10 Inhibiting TGF-b Signalling 265
11 Summary and Future Directions 266
References 266
Receptors and Transporters: Role in Cell Function and Hypoxic Pulmonary Vasoconstriction 341
Mitochondrial Regulation of Oxygen Sensing 342
1 Introduction 342
2 Mitochondria Regulate Oxygen Supply Through an Increase in Hypoxia-Inducible Factor 1 343
3 Mitochondria Regulate Oxygen Demand Through a Decrease in Na/K ATPase Activity 350
4 Controversies in Oxygen Sensing 351
4.1 Do Prolyl Hydroxylases Serve as Oxygen Sensors? 352
4.2 Does Hypoxia Increase the Production of ROS? 353
4.3 Does the Mitochondrial Electron Transport Chain Play a Significant Role in Oxygen Sensing? 353
5 Conclusions and Perspectives 354
References 355
Reactive Oxygen Species and RhoA Signaling in Vascular Smooth Muscle: Role in Chronic Hypoxia-Induced Pulmonary Hypertension 358
1 Chronic Hypoxia Augments RhoA/Rho Kinase-Mediated Ca2+ Sensitization in Pulmonary Vascular Smooth Muscle: A New Paradigm 359
2 RhoA/ROCK Signaling: A Central Component of VSM Ca2+ Sensitization 360
3 Role of RhoA/ROCK in the Development of CH-Induced Pulmonary Hypertension 362
4 Contribution of RhoA/ROCK Signaling to Increased Basal Pulmonary Arterial Tone Following CH 362
5 CH Induces ROCK-Dependent Myogenic Tone in Small Pulmonary Arteries 363
6 Contribution of RhoA/ROCK Signaling to Enhanced Agonist-Induced Pulmonary Vasoreactivity Following CH 364
7 CH Promotes Membrane Depolarization-Induced VSM Ca2+ Sensitization Through a ROCK Signaling Mechanism 366
8 Role of ROS in the Development of PH 367
9 Contribution of ROS to Enhanced Vasoconstrictor Reactivity After CH 368
10 CH Augments ET-1- and Membrane Depolarization-Induced Pulmonary VSM Ca2+ Sensitization Through ROS-Dependent Stimulatio 369
11 Summary and Future Directions 371
References 372
Polyamine Regulatory Pathways as Pharmacologic Targets in Pulmonary Arterial Hypertension 377
1 Pharmacologic Targets in Pulmonary Hypertension 377
2 General Aspects of Polyamine Regulation 379
3 Polyamine Regulation in the Lungs of Rats With Hypoxia- and Monocrotaline-Induced PAH 380
4 Polyamine Synthesis and Transport as Targets for Intervention in PAH 384
5 Summary and Future Directions 386
References 389
5-HT Receptors and KV Channel Internalization 392
1 Introduction 392
2 Serotonin in the Pulmonary Circulation 393
3 Kv Channels in the Pulmonary Circulation 393
4 Regulation of Kv Channels by Pulmonary Vasoconstrictors 395
5 Modulation of Kv Channels by Serotonin 395
6 Signal Compartmentalization 396
7 Role of Internalization 398
8 Summary 399
References 400
Targeting Ion Channels and Membrane Receptors in Developing Novel Therapeutic Approaches for Pulmonary Vascular Disease 403
KCNQ Potassium Channels: New Targets for Pulmonary Vasodilator Drugs? 404
1 Introduction 404
2 Potassium Channels Expressed in Pulmonary Artery 406
3 Potassium Channels, Membrane Potential, and Excitability 408
3.1 The Classical Delayed Rectifier K+ Channels in Pulmonary Artery 409
3.2 Two-Pore-Domain K+ Channels in Pulmonary Artery 409
3.3 The KCNQ (KV7) Voltage-Gated K+ Channels in Pulmonary Artery 411
3.4 Other K+ Channels in Pulmonary Artery 412
4 KCNQ Channels as a Molecular Target for Pulmonary Vasodilators 413
5 Summary 414
References 414
Receptor Tyrosine Kinase Inhibitors in Rodent Pulmonary Hypertension 417
1 Introduction 417
2 Overview of Pulmonary Arterial Hypertension 418
3 Genetic Studies in Pulmonary Hypertension 418
4 New Concepts in PH Pathophysiology – Neoplastic Vasculopathy 419
5 Receptor Tyrosine Kinase Inhibitors as Novel Therapies for Pulmonary Hypertension 419
5.1 Protein Kinase Inhibitor Effects on Growth Factors and Angiogenesis 420
5.2 Sorafenib Effects on Hemodynamic Indices and Vascular Morphology in Rodent PH 421
6 Role of MAPK Pathway Components in Rodent Pulmonary Hypertension 424
7 Effect of Sorafenib on Lung Gene Expression Profiles in Rodent Pulmonary Hypertension 424
8 Comparison of Sorafenib-Modulated Microarray Data Sets with Prior PH Studies 429
9 Caldesmon Studies in Rodent Pulmonary Hypertension (Hypoxia/SU5416-Treated Rats) 429
10 New Directions and Conclusions 431
References 431
PDGF Receptor and its Antagonists: Role in Treatment of PAH 433
1 Introduction 433
2 PDGF Ligands and Receptors 434
3 PDGF-PDGFR-Mediated Intracellular Signal Transduction 435
4 Control of PDGF Signaling 436
5 Expression and Functions of PDGF in the Vascular System 436
6 PDGF Signaling in Vascular Disorders 437
6.1 Atherosclerosis, Restenosis, and Transplant Arteriosclerosis 437
6.2 Pulmonary Hypertension 438
6.3 Cardiotoxicity of Imatinib 441
References 441
PPARg and the Pathobiology of Pulmonary Arterial Hypertension 445
1 Introduction 445
2 Insulin Resistance, Pulmonary Hypertension, and PPARg Agonist Treatment 446
3 PPARg and the Bone Morphogenetic Protein Pathway 448
References 454
Targeting TASK-1 Channels as a Therapeutic Approach 457
1 The TASK Background Two-Pore-Domain Potassium Channels 457
2 TASK-1 Channels in Pulmonary Artery Smooth Muscle Cells 460
3 TASK-1 Is Regulated by Extracellular pH and Possibly Involved in Hypoxic Pulmonary Vasoconstriction 461
4 Hypoxic Pulmonary Vasoconstriction Is Attenuated by Inhaled Anesthetics Due to Activation of TASK-1 Channels 463
5 TASK-1 Is Modulated by G Protein-Coupled Receptor-Activated Pathways 465
References 468
Pharmacological Targets for Pulmonary Vascular Disease: Vasodilation versus Anti-Remodelling 472
1 Current Therapeutic Options 472
2 Mechanisms of Pulmonary Vessel Remodelling 473
3 Novel and Emerging Targets for Anti-remodelling Therapies 474
3.1 Platelet-Derived Growth Factor 474
3.2 RhoA/ROK Pathway 475
3.3 Activin-Like Kinase 5 476
3.4 Anti-inflammatory Targets 477
3.5 Potassium Channels 478
3.6 Notch3 479
3.7 Serotonin 481
4 Conclusions 482
References 484
Index 488