Transient Receptor Potential Channels (eBook)

Preface 7
References 9
Contents 10
Contributors 14
1 Structural Biology of TRP Channels 23
1.1 Introduction 23
1.2 Structure-Determination Methods and Considerations 26
1.3 EM Structures 29
1.4 NMR and X-Ray Crystal Structures 32
1.4.1 TRPM7 -Kinase Domain 32
1.4.2 TRPV Ankyrin Repeats 34
1.4.3 TRPM7 Coiled Coil Domain 36
1.4.4 TRPP2 Coiled Coil Domain 38
1.4.5 TRPP2 C-terminal E-F Hand 39
1.5 Perspectives 41
2 Functional and Structural Studies of TRP Channels Heterologously Expressed in Budding Yeast 46
2.1 Introduction 46
2.2 The TRP Channel Family 47
2.3 Ion Channel Structural Biology 48
2.4 TRP Channels Expression in Saccharomyces cerevisiae and Functional Analysis 49
2.5 Cryo-EM Structures of TRP Channels 51
2.6 Divide and Conquer Approach: Combining X-Ray and EM Data with Computational Modeling 54
2.7 Biochemical Studies with TRP Channels Purified from Yeast 55
2.8 Functional Studies and Genetic Screens of TRP Channels in Yeast 55
2.9 Conclusion 56
3 Natural Product Ligands of TRP Channels 62
3.1 The TRP Family 63
3.2 TRPV1 64
3.2.1 Vanilloids 65
3.2.1.1 Capsaicinoids 65
3.2.1.2 Resiniferanoids 72
3.2.2 a,ß-Unsaturated Dialdehyde 72
3.2.3 Triprenyl Phenols 73
3.2.4 Cannabinoids 74
3.2.5 Ginsenosides 74
3.2.6 Toxins and Peptides 74
3.2.7 Endogenous Ligands 75
3.2.8 Miscellaneous Compounds 76
3.3 TRPV2 76
3.3.1 Cannabinoids 77
3.3.2 Probenecid 77
3.3.3 Endogenous Ligands 77
3.4 TRPV3 77
3.4.1 Monoterpenoids and Diterpenoids 80
3.4.2 Vanilloids 81
3.4.3 Endogenous Ligands 81
3.5 TRPV4 81
3.5.1 Diterpenoids 82
3.5.2 Endogenous Ligands 82
3.6 TRPM8 82
3.6.1 Monoterpenoids 83
3.6.2 Endogenous Ligands 83
3.7 TRPM1 TRPM7 86
3.8 TRPA1 86
3.8.1 Isothiocyanates 87
3.8.2 Thiosulfinates 87
3.8.3 a,ß-Unsaturated Aldehyde 90
3.8.4 Cannabinoids 90
3.8.5 Alkylamides 90
3.8.6 Vanilloids 91
3.8.7 Monoterpenoids 91
3.8.8 Methyl Salicylate 91
3.8.9 Nicotine 91
3.8.10 Endogenous Ligands 91
3.9 TRPC1TRPC6 92
3.10 TRPP2 92
3.11 Conclusions and Future Research 94
4 Synthetic Modulators of TRP Channel Activity 107
4.1 Introduction 107
4.2 Broad-Spectrum Non-natural, Synthetic TRP Channel Blocker 108
4.2.1 SKF-96365 110
4.2.2 2-APB 111
4.2.3 ACA 113
4.2.4 Clotrimazole 114
4.3 TRP Channel-Selective Modulator 115
4.3.1 Compounds Selectively Modulating TRPC Channels 116
4.3.2 Compounds Selectively Modulating TRPM Channels 117
4.3.3 Compounds Selectively Modulating TRPV Channels 117
4.4 Appendix Lanthanum and Gadolinium Ions as Modulators of TRP Channels 118
4.5 Outlook 119
5 Study of TRP Channels by Automated Patch Clamp Systems 127
5.1 Introduction 127
5.2 Results 130
5.2.1 TRPA1 130
5.2.2 TRPCs 132
5.2.2.1 TRPC1 132
5.2.3 TRPMs 132
5.2.3.1 TRPM2 132
5.2.3.2 TRPM3 133
5.2.3.3 TRPM5 134
5.2.3.4 TRPM8 134
5.2.4 TRPVs 135
5.2.4.1 TRPV1 135
5.2.4.2 TRPV4 137
5.3 Conclusions 138
6 TRPC2: Of Mice But Not Men 144
6.1 Introduction 144
6.2 The Regulation of TRPC2 145
6.3 Electrophysiological Properties of TRPC2 146
6.4 Pheromone Signal Transduction in Olfaction 148
6.5 TRPC2 as Regulator of Calcium Entry in Sperm 148
6.6 TRPC2 as Mediator of Erythropoietin-Evoked Signalling 149
6.7 TRPC2 in Rat Thyroid Cells 149
6.8 Perspective 150
7 TRPM1: New Trends for an Old TRP 154
7.1 Introduction 154
7.2 Identification and Characterization of the Melastatin ( MLSN ) Gene 155
7.3 TRPM1 Splice Variants 155
7.4 Regulation of TRPM1 Gene Expression 156
7.5 Tissue and Cellular Distribution of TRPM1 156
7.6 TRPM1 Function 158
7.6.1 TRPM1 Function in Skin 158
7.6.1.1 TRPM1 in Melanoma 158
7.6.1.2 TRPM1 in Melanocyte Pigmentation 158
7.6.2 TRPM1 Function in the Eye 159
7.6.3 TRPM1 is Necessary for Constitutive Currents in Melanocytes and Bipolar Cells 161
7.7 Conclusions 162
8 The Non-selective Monovalent Cationic Channels TRPM4 and TRPM5 165
8.1 Introduction 166
8.2 Molecular Structure 167
8.3 Biophysical and Regulatory Properties 169
8.3.1 Ionic Selectivity 171
8.3.2 Calcium Sensitivity 172
8.3.3 Voltage Sensitivity 172
8.3.4 ATP Sensitivity 173
8.3.5 Thermal, PIP 2 and pH Sensitivity 173
8.4 TRPM4 and TRPM5 Pharmacology 174
8.5 TRPM4 and TRPM5 Physiological Impact 175
8.5.1 TRPM4 Enhances Insulin Secretion by Pancreatic -Cells 176
8.5.2 TRPM4 Promotes the Bayliss Effect in Cerebral Arteries 178
8.5.3 TRPM4 in Immune Cells 178
8.5.4 Modulation of Firing Rate of Breath Pacemaker Neurons 179
8.5.5 TRPM4 in Cardiac Cells 180
8.5.6 TRPM5 as a Taste Transducer 181
8.6 Conclusion and Perspectives 182
9 TRPM7, the Mg 2+ Inhibited Channel and Kinase 190
9.1 Architecture and Expression Pattern 190
9.2 Channel Properties and Regulation 192
9.3 Cellular and Biological Functions of TRPM7 195
9.4 Pathological Functions in Disease Conditions 196
10 TRPM8 in Health and Disease: Cold Sensing and Beyond 201
10.1 Introduction 201
10.2 Gene, Structure/Function and Expression 201
10.3 Biophysical/Pharmacological Properties and Modulation 203
10.4 Physiology/Pathophysiology and Potential as a Therapeutic Target 211
10.4.1 TRPM8 as a Molecular Sensor of Cold Temperatures 211
10.4.2 Potential of TRPM8 as a Therapeutic Target for Chronic Pain 213
10.4.3 Potential of TRPM8 as a Marker and Therapeutic Target for Prostate Cancer 215
10.5 Concluding Remarks 217
11 TRPML1 225
11.1 Introduction: TRPML1 Discovery and Initial Characterization 225
11.2 The Recent Developments 229
11.3 Perspectives 231
12 TRPML2 and the Evolution of Mucolipins 236
12.1 Genomics and Phylogeny 236
12.2 Tissue Distribution 239
12.3 Channel Properties 240
12.4 Subcellular Localization 241
12.5 Subunit Interactions 241
12.6 Biological Roles and Future Directions 242
12.7 Note Added in Proof 242
13 The TRPML3 Channel: From Gene to Function 244
13.1 Genomics of Mcoln3 244
13.2 Normal and Mutant Alleles of Mcoln3 246
13.3 Molecular Physiological Function of TRPML3 247
13.4 TRPML3 and Its Role in the Endocytic Pathway 249
13.5 Open Questions Future Directions 250
14 TRPV5 and TRPV6 in Transcellular Ca 2 +Transport: Regulation, Gene Duplication, and Polymorphisms in African Populations 253
14.1 Identification Results of Seeking Ca 2+ Transporters in Transcellular Pathways 254
14.2 Evolution of the Genes: From One to Two 255
14.3 Roles as Ca 2+ Entry Channel in Active Intestinal/Renal Ca 2 Re/absorption 256
14.3.1 Expression in Ca 2+ Transporting Epithelia 257
14.3.2 Function and Regulation as Ca2+ Entry Channels 258
14.3.3 Robust Regulation by Calcitrophic Hormones 259
14.3.3.1 Vitamin D 259
14.3.3.2 Parathyroid Hormone 260
14.3.3.3 Calcitonin 261
14.3.3.4 Klotho 261
14.3.4 Regulation Under Physiological Conditions 261
14.3.4.1 Low Dietary Ca 2+ 261
14.3.4.2 Pregnancy and Lactation 262
14.3.4.3 Sex Hormones 262
14.3.4.4 Exercise 262
14.3.4.5 Aging 263
14.3.5 Gene Knockout Studies 263
14.4 Roles Beyond Intestinal/Renal Ca2 + Re/absorption 265
14.4.1 TRPV6 in Maternal-Fetal Ca 2+ Transport 265
14.4.2 TRPV6 Expression and Regulation in the Uterus 266
14.4.3 TRPV5 in Bone Resorption 266
14.4.4 TRPV5 and TRPV6 in Maintaining Ca2+Gradient in the Inner Ear 266
14.4.5 TRPV6 in Exocrine Organs 267
14.5 Regulation Under Pathological and Therapeutic Conditions 267
14.5.1 TRPV6 in Cancer 268
14.5.2 TRPV5 and TRPV6 in Pseudohypoaldosteronism Type II 270
14.5.3 Glucocorticoids 271
14.5.4 Diuretics 272
14.6 Unusual High Frequencies of SNPs in African Populations 273
14.7 Perspectives 276
15 The TRPV5 Promoter as a Tool for Generation of Transgenic Mouse Models 290
15.1 Introduction 290
15.2 TRPV5 Promoter Driven EGFP Expressing Mice 292
15.2.1 Mouse Generation 292
15.2.2 Validation of the Transgenic Mouse Lines 293
15.2.3 Studies in TRPV5-EGFP Mice 294
15.2.4 Perspectives 296
15.3 TRPV5 Promoter Driven Cre Recombinase Expressing Mice 296
15.3.1 Generation 296
15.3.2 Validation 297
15.3.3 Perspectives 298
15.4 Conclusion 298
16 TRPP Channels and Polycystins 300
16.1 Introduction 300
16.2 Autosomal Dominant Polycystic Kidney Disease (ADPKD) 302
16.3 Primary Cilia and Polycystic Kidney Disease 303
16.4 The TRPP Family 305
16.5 The Polycystin-1 Family 305
16.6 TRPP2 and PC-1 306
16.7 TRPP3 and PKD1L3 310
16.8 TRPP5 312
16.9 PKDREJ 313
16.10 PKD1L1 314
16.11 PKD1L2 315
16.12 Conclusions 315
17 TRP Channels in Yeast 327
17.1 Microbial Ion Channels 327
17.2 S. cerevisiae TRP Channels 328
17.3 Function of the Yvc1 Channel 329
17.4 Mechanosensation of the Yeast Vacuolar Channel 329
17.5 Molecular Dissection of YVC1 (Also Known as TRPY1) 330
17.6 Yvc1 Homologs in Other Yeast 330
17.7 TRP Homologs in S. pombe 330
17.8 TRPP2 Homologs in Other Yeast 331
17.9 TRPP2 Homologs in S. cerevisiae 331
18 C. elegans TRP Channels 334
18.1 Introduction 334
18.2 Functions of TRP Channels in C. elegans 336
18.3 Activation of TRP Channels in C. elegans 338
18.4 Regulation of TRP Channels in C. elegans 340
18.5 Perspectives 343
18.6 Note Added in Proof 344
19 Investigations of the In Vivo Requirements of Transient Receptor Potential Ion Channels Using Frog and Zebrafish Model Systems 351
19.1 Introduction 352
19.2 TRPC1 Is a Mechanosensitive Cation Channel in Frog Oocytes 353
19.3 TRPC1 Is Involved in Axon Path Finding During Xenopus Embryogenesis 353
19.4 Expression of TRP Channel as a Marker of Cell-Type 354
19.5 Zebrafish Functions of TRPN1 355
19.6 In Zebrafish as in Mouse, TRPA1 Mediates the Response to Noxious Chemicals but Not to Loud Sound or Changes in Temperature 356
19.7 TRPC1 Regulates Angiogenesis Upstream of Map Kinase Activity 357
19.8 TRPP2 Is Necessary to Prevent Cyst Formation in Both Mammals and Zebrafish 358
19.9 A Heteromultimer of TRPV4 and TRPP2 May Be the Mechanosensitive Complex that Detects Deflection of the Primary Cilium 359
19.10 Use of Zebrafish to Test, In Vivo , a Hypothesis Generated Based on a Tissue-Culture Model 359
19.11 Investigation of TRP Channel Evolution During the Transition to a Warm-Blooded Lifestyle 360
19.12 Zebrafish TRPM7 Mutants Reveal a Requirement for TRPM7 in Melanocyte Differentiation 361
19.13 Conclusions 362
20 TRP Channels in Parasites 368
20.1 Introduction 368
20.2 Endoparasites 370
20.2.1 Protozoa 371
20.2.2 Helminths 372
20.2.2.1 Nematodes 372
20.2.2.2 Trematodes and Cestodes 374
20.3 Ectoparasites 375
20.4 Conclusions 375
21 Receptor Signaling Integration by TRP Channelsomes 381
21.1 Introduction 381
21.2 TRPC3 382
21.3 TRPC5 385
21.4 TRPM2 387
21.5 Conclusion 390
22 Gating Mechanisms of Canonical Transient Receptor Potential Channel Proteins: Role of Phosphoinositols and Diacylglycerol 398
22.1 Introduction 398
22.2 TRPC Subunits Produce a Diverse Group of Functional Channel Isoforms 399
22.3 Physiological Gating of TRPC Channels 400
22.4 Activation of Drosophila TRP and TRPL Channels: Models for TRPC Gating 401
22.4.1 Central Role for DAG in Gating Drosophila TRP and TRPL Channels 402
22.5 Mammalian TRPC3/C6/C7 Subunits: Classical DAG-Activated Channels 404
22.5.1 Role of DAG 404
22.5.2 Role of IP 3 405
22.5.3 Interactions Between DAG and PIP 2 406
22.5.4 Direct vs. Indirect Actions of PIP 2 407
22.6 Are TRPC4 and TRPC5 Subunits DAG-Gated Channels 408
22.7 TRPC1 Containing Channels: PKC- and PIP 2 -Activated Channels 409
22.7.1 Role of PKC in Gating of TRPC1 410
22.7.2 Role of PIP2 in Gating of TRPC1 410
22.8 Summary 411
23 The TRPC Ion Channels: Association with Orai1 and STIM1 Proteins and Participation in Capacitative and Non-capacitative Calcium Entry 419
23.1 Introduction 420
23.2 Transient Receptor Potential (TRP) Proteins: TRPCs 422
23.3 STIM and Orai Proteins 423
23.4 STIM1-Orai1-TRPC Communication 426
23.5 Calcium Entry Pathways Mediated by STIM1-Orai1-TRPC Complexes 428
24 Contribution of TRPC1 and Orai1 to Ca 2+ Entry Activated by Store Depletion 440
24.1 Introduction 440
24.2 Characteristics of SOCE 441
24.2.1 Experimental Methods for Activation and Assessment of SOCE 441
24.2.2 Characteristics of the Currents Associated with SOCE 442
24.3 Proposed Molecular Components of SOCE 442
24.3.1 TRPC Channels 442
24.3.2 Orai Channels 443
24.3.3 STIM Proteins 444
24.4 STIM1/Orai1 and CRAC Channels 444
24.5 TRPC1/Orai1/STIM1 and SOC Channels 446
24.6 TRPC-Generated SOC Channels Problems and Perspectives 447
24.7 Conclusions 449
25 Primary Thermosensory Events in Cells 455
25.1 Temperature Sensing Biomolecules 457
25.2 Membrane Lipids Fluidity 458
25.3 RNA and DNA Thermotropic Reactions 459
25.4 Protein Thermometers 460
25.5 Biophysical Aspects of Protein Thermosensitivity 462
25.6 Structural Features of Protein Thermometers 466
26 Thermo-TRP Channels: Biophysics of Polymodal Receptors 473
26.1 Introduction 473
26.2 Energetics of Thermal Activation 476
26.3 Thermal and Voltage Sensitivity of Thermo-TRP 478
26.3.1 Heat-Induced Single-Channel Activity of TRPV1 480
26.3.2 Structural Determinants of Thermal Sensitivity 481
26.3.2.1 TRPV1 481
26.3.2.2 TRPM8 483
26.3.3 Structural Determinants of Voltage-Dependence 483
26.4 TRPV1 and TRPM8 Channel Activation by Agonists 484
26.5 Allosteric Gating in Thermo-TRP 485
26.6 TRPV1 Channels Are Wide Pores and Show Pore Dilation in the Presence of Agonists 487
26.6.1 Other Thermo-TRP Channels Undergo Pore Dilation 489
26.7 Where Is the Activation Gate? 489
26.8 Coda 490
27 Complex Regulation of TRPV1 and Related Thermo-TRPs: Implications for Therapeutic Intervention 495
27.1 Introduction 495
27.2 TRPV1 and Nociception 497
27.3 Molecular Mechanisms of TRPV1 Desensitization 499
27.3.1 TRPV1 Dephosphorylation 501
27.3.1.1 PKA Sites 501
27.3.1.2 PKC Sites 503
27.3.1.3 CamKII Sites 503
27.3.1.4 Interaction with Calmodulin 504
27.3.1.5 Depletion of PIP2 505
27.4 Physiological Functions of TRPV1 Desensitization 506
27.5 Molecular Mechanisms of TRPV1 Sensitization 507
27.6 Modulation of TRPV1 by Signalling Complexes (Signalplex) 508
27.6.1 Scaffolding Proteins 509
27.6.2 Signalling Proteins 510
27.6.3 Trafficking Proteins 511
27.7 Outlook 513
28 Voltage Sensing in Thermo-TRP Channels 520
28.1 TRP Channel Family and Thermo-TRPs 520
28.2 The Process of Channel Gating 521
28.3 Voltage Dependence 522
28.4 Temperature Activation 524
28.5 Allosteric Models and Thermo-TRP Channel Activation 527
28.6 Final Words 531
29 TRP Channels as Mediators of Oxidative Stress 534
29.1 Introduction 535
29.2 TRPC in Oxidative Stress 536
29.3 TRPM in Oxidative Stress 537
29.3.1 TRPM2 537
29.3.2 TRPM7 541
29.4 TRPV in Oxidative Stress 542
29.5 Future Perspectives 543
30 Regulation of TRP Signalling by Ion Channel Translocation Between Cell Compartments 548
30.1 Introduction 550
30.2 Signalling Pathways Regulating Translocation of TRPC Channels 550
30.3 Signalling Pathways Regulating Translocation of TRPV Channels 559
30.4 Signalling Pathways Regulating Translocation of TRPM Channels 565
30.5 Signalling Pathways Regulating Translocation of TRPA1 566
30.6 Proteins Regulating the Localization of TRPP2 and TRPML Channels 567
30.7 Conclusion and Future Perspectives 568
31 Emerging Roles of Canonical TRP Channels in Neuronal Function 576
31.1 Introduction 576
31.2 Physiological Importance of Canonical TRP Channels in Neurons 578
31.2.1 TRPC1 579
31.2.2 TRPC2 581
31.2.3 TRPC3 581
31.2.4 TRPC4 583
31.2.5 TRPC5 584
31.2.6 TRPC6 585
31.2.7 TRPC7 587
31.3 TRPC Proteins in Neurodegenerative Diseases 587
31.4 TRPC Channels and Oxidative Stress 589
31.5 Concluding Remarks 589
32 TRP Channels and Neural Persistent Activity 597
32.1 Introduction 597
32.2 Mechanisms of Persistent Activity 598
32.2.1 Non-specific Ca 2+ Sensitive Cationic Current (CAN Current) 598
32.3 TRP Channels and CAN Current 600
32.4 TRPC Channels and G-Protein Mediated Receptors 601
32.5 TRPC Channels and PLC 602
32.6 TRPC and PIP2 602
32.7 TRPC and IP3 603
32.8 TRPC and Ca 2+ Channels 603
32.9 TRPC and DAG 604
32.10 TRPC Pharmacology 604
32.11 TRP and Diseases Epilepsy 605
32.12 TRP, Pain Processing and Persistent Activity 605
32.13 Future Directions 606
33 Role of TRP Channels in Pain Sensation 616
33.1 Introduction 616
33.2 TRPV1 617
33.2.1 Unequivocal Role in Heat Pain and Thermal Hyperalgesia 617
33.2.2 Role of TRPV1 in Deep Tissue Pain 619
33.2.3 The Role of TRPV1 in Central Terminals of Primary Afferents and Central Nervous System (CNS) 619
33.2.4 Therapeutic Approaches Targeting TRPV1 621
33.2.4.1 Agonists of TRPV1 622
33.2.4.2 Selective Antagonists of TRPV1 622
33.2.4.3 Selective Silencing of Nociceptors Through TRPV1 623
33.3 TRPA1 624
33.3.1 TRPA1 Senses Tissue Damages 624
33.3.2 The Role of TRPA1 in Cold Pain and Hyperalgesia 625
33.3.3 The Role of TRPA1 in Mechanical Hyperalgesia 626
33.3.4 TRPA1 Induces Heterologous Desensitization of TRPV1 626
33.4 TRPM8 627
33.5 TRPV3 and TRPV4 628
33.6 Perspectives 629
34 TRPV1: A Therapy Target That Attracts the Pharmaceutical Interests 638
34.1 Gene and Protein Structure of TRPV1 638
34.1.1 Identification of the TRPV1 as an Ion Channel 638
34.1.2 From Gene to Structure 639
34.2 Expression Pattern and Biological Function of TRPV1 640
34.2.1 Tissue Distribution 640
34.2.2 Modulation of Expression 641
34.2.3 Physiological and Pathological Roles of TRPV1 641
34.2.3.1 Pain and Temperature Sensation 641
34.2.3.2 Respiratory Diseases 641
34.2.3.3 Vascular and Renal Hypertension 642
34.2.3.4 Urinary Bladder 642
34.3 Ion Channel Properties 642
34.3.1 Activation 642
34.3.2 Gating Biophysics 643
34.3.3 Ion Selectivity and Permeability 644
34.3.4 Modulation of TRPV1 Function 644
34.4 Research Toolkits 645
34.4.1 Current Methods for TRPV1 Production and Purification 645
34.4.2 Radio Ligand Binding Assays 645
34.4.3 Electrophysiology: Manual and Automated Patch Clamp Recordings 646
34.4.4 Florescence Imaging and 45 Ca 2+ Flux Assays 646
34.5 Pharmacology and Druggability 647
34.5.1 Agonists of TRPV1 647
34.5.2 Antagonists of TRPV1 648
34.5.3 Clinical Status of TRPV1-Targeted Therapies 648
34.5.3.1 Neurogesx Has Qutenza0 in Phase-III (NGX-4010 Dermal Patch (8 0 0 Capsaicin)) 648
34.5.3.2 Anesiva Has Adlea in Phase-III (AlgrX-4975 Injectable/Intraarticular) 652
34.5.3.3 Winston Laboratories Has Civamide in Phase-III (Inhaled/Injectable) 652
34.6 Future Prospect 655
34.6.1 Modality Specific TRPV1 Antagonists 655
34.6.2 Biologics: Antibodies and Toxins 656
34.6.3 Structure-Guided Drug Discovery 656
34.6.4 Concluding Remarks 657
35 Expression and Function of TRP Channels in Liver Cells 667
35.1 Introduction 667
35.2 TRP Channels Expressed in the Liver 670
35.3 TRP Proteins and Store-Operated Ca2 + Entry in Hepatocytes 672
35.4 Physiological Functions of TRP Channels in Hepatocytes and in Hepatocyte (Liver) Cell Lines 674
35.4.1 TRPV1 and TRPV4 in Cell Migration 674
35.4.2 TRPC1 and Volume Control 674
35.4.3 TRPM7 and Cell Proliferation 675
35.4.4 TRPML1 and Lysosomal Ca 2+ Release 675
35.4.5 Other TRP Channels in Hepatocytes and in Hepatocyte (Liver) Cell Lines: Possible Functions 676
35.5 TRP Channels in Other Cell Types Present in the Liver 677
35.6 TRP Channels and Liver Cancer 677
35.7 Conclusions 678
36 Expression and Physiological Roles of TRP Channels in Smooth Muscle Cells 687
36.1 Introduction 687
36.2 Expression of TRP in SMC 688
36.2.1 TRPC 689
36.2.2 TRPV 689
36.2.3 TRPM 690
36.2.4 TRPP 691
36.3 Physiological and Pathophysiological Roles of TRP in SMC 691
36.3.1 TRP and the Vascular System 692
36.3.1.1 TRP and Vascular SMC Growth and Hyperplasia 692
36.3.1.2 TRP in Vascular Contractile Function in Physiological and Pathophysiological Conditions 692
36.3.2 TRP and Gastro Intestinal Tract 697
36.3.2.1 TRP in Intestinal Motility 697
36.3.2.2 TRPM8 and Gatric Activity 698
36.3.3 TRP and Uterine Contractile Activity 698
36.4 Conclusion 699
37 TRPM Channels in the Vasculature 707
37.1 Introduction 708
37.2 TRPM Channels 710
37.2.1 Channel Structure 710
37.2.2 Biophysical Properties 710
37.2.3 Activation Mechanisms and Functional Roles 712
37.2.3.1 TRPM1 712
37.2.3.2 TRPM2 712
37.2.3.3 TRPM3 713
37.2.3.4 TRPM4 and TRPM5 713
37.2.3.5 TRPM6 and TRPM7 714
37.2.3.6 TRPM8 714
37.2.4 Roles of G-Protein Coupled Receptors (GPCR) and Ca 2+ Store Depletion in TRPM Regulation 714
37.2.5 Pharmacological Properties of TRPM Channels 715
37.3 TRPM Channels in Vascular Function and Disease 716
37.3.1 TRPM Expression in Endothelial and Vascular Smooth Muscle Cells 716
37.3.2 Specific Vascular Functions of TRPM Channels 717
37.3.2.1 TRPM2 Role in Oxidant Stress and Endothelial Permeability 717
37.3.2.2 TRPM4 and Myogenic Tone 717
37.3.2.3 TRPM7 Role in Magnesium Homeostasis and Hypertension 718
37.3.2.4 TRPM8 Role in Thermal Behaviour of Blood Vessels 719
37.4 Conclusions 723
38 Molecular Expression and Functional Role of Canonical Transient Receptor Potential Channels in Airway Smooth Muscle Cells 730
38.1 Introduction 730
38.2 Multiple TRPC Molecules are Expressed in Airway SMCs 731
38.3 TRPC3 Is an Important Molecular Component of Native Constitutively-Active NSCCs in Airway SMCs 732
38.4 TRPC3-Encoded NSCCs are Important for Controlling the Resting Membrane Potential and [Ca 2 ] i in Airway SMCs 733
38.5 TRPC3-Encoded NSCCs May Mediate Agonist-Induced Increase in [Ca 2 ] i in Airway SMCs 735
38.6 TRPC-Encoded NSCCs Cause Ca2+ Influx Through Themselves Directly, Na +/Ca2+ Exchanger-1 and/or L-type Ca2+ Channels in Airway SMCs 736
38.7 TRPC-Encoded NSCC-Mediated Ca 2+ Influx Occurs Due to Store-Operated Ca 2+ Entry, Receptor-Operated Ca2 + Entry, or Both Processes in Airway SMCs 737
38.8 TRPC3-Encoded Native Constitutively-Active NSCCs are Significantly Upregulated in Expression and Activity in Asthmatic Airway SMCs 738
38.9 Perspective 740
39 TRP Channels in Skeletal Muscle: Gene Expression, Function and Implications for Disease 747
39.1 Calcium Entry Pathways in the Sarcolemma of Skeletal Muscle Fibres 747
39.2 Linking Physiologically Detected Cation Channels to TRP Channel Proteins 748
39.3 Gene Expression of TRP Channels in Mammalian Skeletal Muscle 749
39.4 Localization and Function of TRP Channels 750
39.4.1 The TRPC Subfamily 750
39.4.2 The TRPV Subfamily 752
39.4.3 The TRPM Subfamily 753
39.5 Implications for Disease 753
40 TRP Channels in Vascular Endothelial Cells 757
40.1 Introduction 757
40.2 Expression of TRP Isoforms in Endothelial Cells 758
40.3 Functional Role of Endothelial TRP Channels 761
40.3.1 Ca 2+ Influx and Electrogenesis 761
40.4 Control of Vascular Tone 763
40.5 Control of Vascular Permeability 764
40.6 Angiogenesis and Blood Vessel Formation 765
40.7 Oxidative Stress 767
40.8 Mechanosensing 768
40.9 TRP Channels, Endothelial Dysfunction, Diseases 770
40.10 Conclusive Remarks and Goal for Future 771
41 TRP Channels in the Cardiopulmonary Vasculature 779
41.1 Introduction 779
41.1.1 TRPA Channels 780
41.1.2 TRPC Channels 780
41.1.3 The TRPM Family 782
41.1.4 The TRPP Family 783
41.1.5 TRPV Channels 783
41.2 TRP Expression in the Heart: Physiological Function and Pathophysiological Implications 784
41.3 TRP Expression and Function in Endothelial Cells of the Systemic and Pulmonary Circulation 789
41.4 Expression and Pathological Overexpression of TRPC Channels in Smooth Muscle Cells of the Systemic Vasculature 794
41.5 Conclusion 798
42 TRP Channels of Islets 809
42.1 Introduction 809
42.2 TRPM4 and TRPM5 812
42.2.1 Role of TRPM4 and TRPM5 in Stimulus-Secretion Coupling in -Cells 813
42.3 TRPM2 (Formerly Called LTRPC2) 815
42.3.1 TRPM2 and -Cells 815
42.3.2 Role of TRPM2 Channel in Stimulus-Secretion Coupling in -Cells 815
42.3.3 Heat as a Physical Second Messenger 817
42.3.4 TRPM2 and -Cells Death 818
42.3.5 TRPM2 as an Intracellular Ca2+ Release Channel 818
42.4 TRPM3 818
42.5 TRPV4 (Other Names OTRPC4, VR-OAC, VRL-2, TRP-12) 819
42.6 TRPV2 820
42.7 TRPV1 821
42.8 TRPC1 and TRPC4 821
42.9 Perspectives 822
43 Multiple Roles for TRPs in the Taste System: Not Your Typical TRPs 829
43.1 Introduction 829
43.2 TRP-Melastatin 5 (TRPM5) 832
43.3 Polycystic Kidney Disease-1-Like 3/Polycystic Kidney Disease-2-Like 1 (PKD1L3/PKD2L1) TRPP Channels 834
43.4 Vanilloid Receptor 1 (TRPV1) 836
43.5 Conclusions 839
44 Roles of Transient Receptor Potential Proteins (TRPs) in Epidermal Keratinocytes 845
44.1 Expression of TRPs in Epidermal Keratinocytes 845
44.2 Role of TRPs in Keratinocyte Differentiation 846
44.3 Role of TRPs in Cutaneous Inflammation and Epidermal Proliferation 848
44.4 Role of TRPs in Epidermal Permeability Barrier Homeostasis 849
44.5 TRPs in Hair and Sebaceous Gland 851
44.6 Keratinocyte TRPs as a Cutaneous Sensory System 851
44.7 Epidermal Keratinocytes as the Interface Between Body and Environment 852
45 TRP Channels in Urinary Bladder Mechanosensation 859
45.1 Introduction 859
45.2 Mechanosensory Machinery in the Urinary Bladder 860
45.2.1 Sensory Nerve Endings 860
45.2.2 Urothelium 862
45.2.3 Detrusor Smooth Muscle and Interstitial Cells of Cajal 863
45.3 TRP Channels in the Urinary Bladder 864
45.3.1 TRPV1 864
45.3.2 TRPM8 865
45.3.3 TRPA1 866
45.3.4 TRPV4 866
45.3.5 TRPV2 and Other Mechanosensitive TRP Channels 867
45.4 Other Mechanosensitive Channels in the Urinary Bladder 867
45.4.1 Degenerin/Epithelial Na + Channel Family 867
45.4.2 Two-Pore-Domain K+ Channels 868
45.5 Summary 869
46 The Role of TRP Ion Channels in Testicular Function 878
46.1 Introduction 878
46.2 TRPC Family 879
46.3 TRPP Family 888
46.4 TRPV Family 889
46.5 TRPM 890
46.6 Conclusions 891
47 TRP Channels in Female Reproductive Organs and Placenta 906
47.1 Introduction 906
47.2 The TRPC Family 907
47.3 The TRPV Family 911
47.3.1 TRPV1 911
47.3.2 TRPV2/TRPV3 912
47.3.3 TRPV4 912
47.3.4 TRPV5/6 914
47.4 The TRPM Family 915
47.5 TRPP Family 916
47.6 Mammary Glands 918
47.7 Conclusion 918
48 Oncogenic TRP Channels 926
48.1 Introduction 926
48.2 Role of TRP Channels in Cancer Development and Progression 927
48.2.1 TRPC Channels and Cancer 928
48.2.2 TRPV Channels and Cancer 930
48.2.3 TRPM Channels and Cancer 934
48.3 Conclusions 936
49 TRPV Channels in Tumor Growth and Progression 943
49.1 Introduction 944
49.2 TRPV1 945
49.3 TRPV2 950
49.4 TRPV3 952
49.5 TRPV4 952
49.6 TRPV5 954
49.7 TRPV6 954
49.8 Conclusions and Perspectives 956
50 The Role of Transient Receptor Potential Channels in Respiratory Symptoms and Pathophysiology 964
50.1 Sensory Neuronal TRP Channels as Initiators and Regulators of Respiratory Symptoms 965
50.1.1 Transient Receptor Potential Vanilloid 1: A Capsaicin-Sensitive Polymodal Respiratory Irritant Sensor 965
50.1.2 Transient Receptor Potential Ankyrin 1: A Unique, Polymodal Sensor of Noxious Irritants 967
50.1.3 Transient Receptor Potential Melastatin 8: The Cold and Menthol Receptor 968
50.2 TRP Channels in Airway Cells of Non-Neuronal Origin 969
50.2.1 TRPA1 as a Calcium-Permeable Ion Channel in Human Pulmonary Fibroblasts 969
50.2.2 TRPC Channels Regulate Intracellular Calcium Homeostasis and Inflammation 970
50.2.3 Wide-Ranging Functions of TRPM Channels in Airway Structural and Immune Cells 970
50.2.4 TRPV Channels: Beyond the Capsaicin Receptor 971
50.2.5 Summary 973
51 TRP Channels and Psychiatric Disorders 982
51.1 Introduction 982
51.2 TRP Channels in the Brain 983
51.2.1 TRPC Channels 983
51.2.2 TRPV Channels 984
51.3 Depression and Anxiety 985
51.3.1 TRPC Channels, Depression and Anxiety 986
51.3.2 TRPV Channels, Depression and Anxiety 987
51.4 Schizophrenia 989
51.4.1 TRPC Channels and Schizophrenia 990
51.4.2 TRPV Channels and Schizophrenia 991
51.5 Conclusion 995
52 Transient Receptor Potential Genes and Human Inherited Disease 1005
52.1 Introduction 1005
52.2 The Canonical TRPs 1006
52.2.1 TRPC6 1006
52.3 The Vanilloid TRPs 1007
52.3.1 TRPV4 1008
52.3.1.1 Skeletal Disorders 1008
52.3.1.2 Neuromuscular Disorders 1010
52.4 The Melastatin TRPs 1011
52.4.1 TRPM1 1011
52.4.1.1 Congenital Stationary Night Blindness 1011
52.4.2 TRPM4 1014
52.4.2.1 Progressive Familial Heart Block, Type 1B 1014
52.4.3 TRPM6 1014
52.4.3.1 Hypomagnesaemia with Secondary Hypocalcaemia 1014
52.5 The Polycystin TRPs 1017
52.5.1 TRPP1=PKD2 1017
52.6 The Mucolipin TRPs 1019
52.6.1 TRPML1 1019
52.7 Summary 1021
Erratum 1027
Index 1028