ISBN: 3-540-66127-1
TITLE: Pharmacology of Ionic Channel Function: Activators and Inhibitors
AUTHOR: Endo, M.; Kurachi, Y.; Mishina, M. (Eds.)
TOC:

Section I: Voltage-Dependent Ion Channels
A. Voltage-Dependent Na Channels 1
CHAPTER 1
Structure and Functions of Voltage-Dependent Na^+ Channels
K. Imoto. With 3 Figures 3
A. Introduction 3
B. General Architecture 4
C. alpha Subunit 4
I. Brain Types I, II, and III 7
1. Brain Type II/IIA 7
2. Brain Type I 8
3. Brain Type III 9
II. Skeletal Muscle I/SkM1/SCN4A 9
III. Heart I/SkM2/hH1/SCN5A 9
IV. NaCh6 (Rat)/Scn8a (Mouse)/PN4 10
V. PN1/Na_s/hNE-Na/Scn9a 12
1. hNE-Na 12
2. Na_s 12
3. PN1 12
VI. SNS/PN3/NaNG/Scn10a 13
1. SNS/PN3/Scn10a 13
2. NaNG 13
VII. NaN/SNS2 13
VIII. Atypical Sodium Channels 14
1. hNa_v2.1 14
2. mNa_v2.3 14
3. SCL-11 14
D. Accessory Subunits 15
I. beta1 Subunit 15
II. beta2 Subunit 15
III. Other Associated Proteins 16
1. TipE 16
2. Ankyrin_G 16
3. AKAP15 17
4. Syntrophins 17
5. Extracellular Matrix Molecules 17
E. Genomic Structure 17
F. Concluding Remarks 17
References 19
CHAPTER 2
Sodium Channel Blockers and Activators
A.O. Grant. With 3 Figures 27
A. Introduction 27
B. Classification and Structure of Na^+ Channels 27
C. Mechanisms of Na^+ Channel Blockade by Antiarrhythmic drugs 30
D. Models of Antiarrhythmic Drug Interaction with the Sodium Channel 32
E. The Highly Specific Na^+ Channel Blockers TTX and STX 38
F. Peptide Na Channel Blockers:  Conotoxins 41
G. Na Channel Activators 42
H. Conclusions 45
References 45
B. Voltage-Dependent Ca-Channels
CHAPTER 3
Classification and Function of Voltage-Gated Calcium Channels
J.B. Bergsman, D.B. Wheeler, R.W. Tsien. With 2 Figures 55
A. Generic Properties of Voltage-Gated Ca^{2+} Channels 55
I. Basic Functional Properties 55
II. Subunit Composition 56
1. alpha_1 57
2. beta 57
3. alpha_2/delta 58
4. gamma 58
B. Classification of Native Ca^{2+} Channels According to Biophysical, Pharmacological, and Molecular Biological Properties 58
I. Molecular Biological Nomenclature 59
II. Ca_v1/L-Type Ca^{2+} Channels 59
III. Ca_v2 61
1. Ca_v2.2/N-Type Ca^{2+} Channels 61
2. Ca_v2.1/P- and Q-Type Ca^{2+} Channels 62
3. Ca_v2.3/R-Type Ca^{2+} Channels 63
IV. Ca_v3/T-Type Ca^{2+} Channels 64
V. Note on Pharmacology 65
VI. Evolutionary Conservation of Ca^{2+} Channel Families 65
C. Functional Roles of Ca^{2+} Channels 66
I. Introduction/Subcellular Localization 66
II. Excitation-Contraction Coupling 66
III. Rhythmic Activity 67
1. Pacemaker 67
2. Other 67
IV. Excitation-Secretion Coupling 68
1. Generic Properties 68
2. Peripheral 69
3. Central 70
V. Postsynaptic Ca^{2+} Influx 71
1. Dendritic Information Processing 71
2. Excitation-Expression Coupling and Changes in Gene Expression 72
D. Concluding Remarks 73
References 73
CHAPTER 4
Structure of the Voltage-Dependent L-Type Calcium Channel
F. Hofmann, N. Klugbauer. With 3 Figures 87
A. Introduction 87
B. Subunit Composition and Genes of the Calcium Channel Complex 87
I. Subunit Composition of L-Type Calcium Channels 87
II. Genes 87
1. The alpha_1 Subunit 87
a) The L-Type alpha_1 Channels 89
alpha) The Class S alpha_1 Gene 89
beta) The Class C alpha_1 Gene 89
gamma) The Class D alpha_1 Gene 89
delta) The Class F alpha_1 Gene 90
b) The None L-Type alpha_1 Channels 90
alpha) The Class A alpha_1 Gene 90
beta) The Class B alpha_1 Gene 90
gamma) The Class E alpha_1 Gene 90
c) The Low Voltage-Activated alpha_1 Channels 90
a) The Class G and H Gene 90
2. Auxiliary Subunits of the Calcium Channel 91
a) The alpha_2delta Subunit 91
b) The beta-Subunit 92
c) The gamma Subunit 93
III. Functional Domains of the alpha_1 Subunit 94
1. The Pore and Ion Selectivity Filter 94
2. Channel Activation 95
3. Channel Inactivation 96
IV. Sites for Interaction with Other Proteins 98
1. Interaction of the alpha_1 Subunit with the Ryanodine Receptor 98
2. Interaction of the alpha_1 Subunit with the beta Subunit 99
V. Binding Sites for L-Type Calcium Channel Agonists and Antagonists 100
1. The Dihydropyridine Binding Site 100
2. The Phenylalkylamine and Benzothiazepine Binding Site 103
3. Modulation of Expressed L-Type Calcium Channel by cAMP-Dependent Phosphorylation 104
4. Modulation of Expressed L-Type Calcium Channel by Protein Kinase C-Dependent Phosphorylation 106
References 107
CHAPTER 5
Ca^{2+} Channel Antagonists and Agonists
S. Adachi-Akahane, T, Nagao. With 9 Figures 119
A. Ca^{2+} Channel Antagonists 119
I. Historical Background 119
II. Allosteric Interaction Between Ca^{2+} Channel Antagonist Binding Sites 121
III. Biophysical and Pharmacological Properties of Ca^{2+} Channel Antagonists 127
1. Dihydropyridines 128
2. Phenylalkylamines 130
3. Benzothiazepines 131
4. Other Ca^{2+} Channel Antagonists 132
IV. Binding Sites 133
1. Electrophysiological Identification of Binding Sites for Ca^{2+} Channel Blockers 133
2. Biochemical Characterization of Drug- Ca^{2+} Channel Interaction: Photoaffinity Labeling of Ca^{2+} Channels 135
3. Molecular Biological Characterization of Drug- Ca^{2+} Channel Interaction: Studies with Experimental Ca^{2+} Channel Mutants 135
B. Inorganic Blockers 138
C. Natural Toxins and Alkaloids 139
D. Ca^{2+} Channel Agonists 142
I. DHPs 142
II. Non-DHPs 144
E. Concluding Remarks 144
References 145
C. Voltage-Dependent K-Channels
CHAPTER 6
Overview of Potassium Channel Families: Molecular Bases of the Functional Diversity
Y. Kubo. With 7 Figures 157
A. Introduction 157
B. Primary Structure of the Main Subunit 157
I. 6-Transmembrane (TM) Type 157
II. 2-TM Type 158
III. 1-TM Type 158
IV. 2-Repeat Type 159
C. Heteromultimeric Assembly: Bases of Further Diversity 159
I. Heteromultimer Formation with Other Members of the Same Subfamily 159
1. Kv Channels 159
2. GIRK1,2,4 159
II. Suppression of Functional Expression by Heteromultimeric Assembly 160
III. Heteromultimeric Assembly of Main Subunits of Different Families 160
IV. Assembly with beta Subunit 160
V. Assembly with Regulatory Subunits 161
VI. Assembly with Anchoring Protein 162
D. Structural Bases of the Gating Mechanism 162
I. Activation of Kv Channels 162
II. N-Type Inactivation of Kv Channels 163
III. C-Type Inactivation of Kv Channels 164
IV. Activation of IsK 165
E. Structural Bases of the Ion Permeation and Block 165
I. H5 Pore Region 165
II. Re-evaluation 165
III. Inward Rectification Mechanism 166
IV. Direct Structure Analysis 168
F. Structural Bases of Various Regulation Mechanisms 168
I. Gbeta gamma 168
II. Block by Cytoplasmic ATP 169
III. Regulation by Phosphorylation 169
IV. Mg^{2+} as a Cytoplasmic Second Messenger 170
V. Regulation by Extracellular K^+ 170
VI. Other Mechanisms 170
G. Perspectives 170
References 171
CHAPTER 7
Pharmacology of Voltage-Gated Potassium Channels
O. Pongs, C. Legros. With 8 Figures 177
A. Introduction 177
B. Molecular and Functional Organization of the Voltage-Gated Potassium Channels 178
I. Structural Domains in Kvalpha-Subunits 178
II. Modulatory Kvbeta-Subunits 181
C. Peptide Toxin Binding Sites182
I. Scorpion Toxins 182
II. Snake Toxins 186
III. Sea Anemone Toxins 188
IV. Snail Toxins 189
V. Spider Toxins 190
D. Conclusions 191
References 191
CHAPTER 8
Voltage-Gated Calcium-Modulated Potassium Channels of Large Unitary Conductance: Structure, Diversity, and Pharmacology
R. Latorre, C. Vergara, E. Stefani, L.Toro. With 2 Figures 197
A. Introduction 197
B. Channel Structure 198
C. Auxiliary Subunits 204
D. Calcium Sensitivity and Diversity of BK_{Ca} Channels in Different Cells and Tissues 205
E. Ca^{2+} Sensing Domain(s): The Calcium Bowl 207
F. Origin of Voltage Dependence in BK_{Ca} Channels 208
G. Channel Inactivation 209
H. Metabolic Modulation 210
I. Pharmacology 211
I. BK_{Ca} Channels Blockers 211
1. Toxins 211
2. Organic Blockers 212
a. Tetraethylammonium 212
b. Indole Diterpenes 213
c. General Anesthetics 213
II. BK_{Ca} Channel Activators 213
1. Activators Isolated from Desmodium adscendens: A Medicinal Herb 213
2. Anti-Inflamatory Aromatic Compounds (Fenamates) 214
3. Benzimidazolones 214
4. Phloretin 214
5. Ethanol 214
J. Summary and Conclusions 215
References 215
CHAPTER 9
Classical Inward Rectifying Potassium Channels: Mechanisms of Inward Rectification
C.G. Nichols. With 3 Figures 225
A. The Nature of Inward Rectification: Classical Considerations 225
B. The Inward Rectifier Ion Channel Family: Two Transmembrane Domain Potassium Channels 227
I. Kir 1 Subfamily 227
II. Kir 2 Subfamily 228
III. Kir 3 Subfamily 228
IV. Kir 4 and 5 Subfamilies 228
V. Kir 6 Subfamily 229
VI. KirD  a New Family of Double-Pored Inward Rectifier Channels? 229
VII. Inward Rectification in Other K^+ Channels 229
C. The Mechanism of Inward Rectification: Pore Block and Intrinsic 230
D. The Structure of the Kir Channel Pore: Binding Sites for Polyamines 231
E. The Structural Requirements for Inward Rectification: The Blocking Particles 233
F. The Physiological Significance of Polyamine-Induced Rectification 236
References 236
CHAPTER 10
ATP-Dependent Potassium Channels in the Kidney
G. Giebisch, W. Wang, S.C. Hebert. With 13 Figures 243
A. Introduction 243
B. The Function of ATP-Sensitive K Channels in the Proximal Tubule 243
C. The Function of ATP-Sensitive K Channels in the Thick Ascending Limb (TAL) of Henle's Loop 245
D. The Function of ATP-Sensitive K Channels in the Cortical Collecting Duct (CCD) 247
E. The Regulation of ATP-Sensitive K Channels 248
I. Proximal Tubule 248
II. Thick Ascending Limb of Henle's Loop 249
III. Cortical Collecting Tubules  Apical Membrane of Principal Cells 250
F. Properties of Cloned ATP-Sensitive K Channels (ROMK) 252
I. Channel Structure 252
II. Channel Isoforms and Localization 254
III. Comparison of ROMK with the Native Secretory ATP-Sensitive K Channel 256
IV. The Channel Pore-Rectification 256
V. Regulation by Phosporylation: Protein Kinase A (PKA) 257
VI. Regulation by Phosphorylation: Protein Kinase C (PKC) 259
VII. Regulation by Nucleotides 259
VIII. Regulation by Interaction with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) 260
IX. Regulation by pH 260
X. Regulation by Phosphoinositides 262
XI. Regulation of ROMK Density in CCD 262
G. ROMK and Bartter's Syndrome 263
References 264
CHAPTER 11
Structure and Function of ATP-Sensitive K^+ Channels
T. Gonoi, S. Seino. With 5 Figures 271
A. Introduction 271
B. Properties of K_{ATP} Channels in Native Tissues 272
I. Heart 272
II. Skeletal Muscles 273
III. Pancreatic beta-Cells 273
IV. Brain 274
V. Smooth Muscles 275
VI. Kidney 275
VII. Mitochondria 276
C. Structure and Functional Properties of Reconstituted KATP Channels 276
I. The Pancreatic beta-Cell Type K_{ATP} Channel 276
1. The Inwardly Rectifying K^+ Channel Subfamily Kir6.0 276
2. The Sulfonylurea Receptor SUR1 277
3. Reconstitution of the Pancreatic beta-Cell Type K_{ATP} Channel 281
II. The Cardiac and Skeletal Muscle Type K_{ATP} Channel 283
1. The Sulfonylurea Receptor SUR2A 283
2. Reconstitution of the Cardiac and Skeletal Muscle Type K_{ATP} Channel 283
III. The Smooth Muscle Type K_{ATP} Channel 283
1. The Sulfonylurea Receptor SUR2B 283
2. Reconstitution of the Smooth Muscle Type K_{ATP} Channel 283
IV. The Vascular Smooth Muscle Type K_{ATP} Channel 284
1. Reconstitution of the Vascular Smooth Muscle Type K_{ATP}Channel 284
D. Physical Interaction and Stoichiometry of the Pancreatic beta-Cell Type K_{ATP} Channel Subunits 284
I. Physical Interaction Between the SUR1 Subunit and the Kir6.2 Subunit 284
II. Subunit Stoichiometry of the SUR1/Kir6.2 Channel 285
E. Domains Conferring Sensitivities to the Nucleotides and Pharmacological Agents 285
I. ATP-Sensitivity 285
II. Nucleotide Diphosphate (NDP)-Sensitivity 286
III. Diazoxide-Sensitivity 286
IV. Sulfonylurea-Sensitivity 287
V. Mg^{2+}- and Spermin-Sensitivity 287
VI. Phentolamine-Sensitivity 287
VII. G-Protein Sensitivity 287
F. Pathophysiology of the Pancreatic beta-Cell K_{ATP} Channel 288
I. Persistent Hyperinsulinemic Hypoglycemia of Infancy 288
II. Transgenic Mice 288
G. Conclusions 288
References 289
CHAPTER 12
G Protein-Gated K^+ Channels
A. Inanobe, Y. Kurachi*. With 11 Figures 297
A. Introduction 297
B. Acetylcholine-Activation of Muscarinic K^+ Channels 298
I. G Protein's Cyclic Reaction 299
II. Positive Cooperative Effect of GTP on the Muscarinic K+ Channel Activity 302
III. Incorporation of Receptor-G Protein Reaction to the Model of K_{ACh} Channel 304
C. Molecular Analyses of G Protein-Gated K^+ Channels 305
I. Cloning of Inwardly Rectifying K^+ Channels and Kir Subunits for G Protein-Gated K^+ Channels 305
II. GIRK Subfamily 307
III. Expression of GIRK Channels 309
IV. Tetrameric Structure of Kir Channels 312
V. Molecular Mechanism Underlying Activation of the G Protein-Gated K^+ Channels by beta gamma Subunits of G Protein 313
1. The G Protein beta gamma Subunit-Binding Domains in GIRK Subunits 313
2. Putative Mechanism Underlying the G Protein beta gamma Subunit-Induced Activation of the G Protein-Gated K^+ Channels 316
3. PIP_2-Mediation of G_{beta gamma}-Activation of K_G Channels 316
VI. The Possible Role of G Protein alpha Subunits in the G Protein-Gated K^+ Channel Regulation 317
1. Possibility of Microdomain Composed of Receptor, G Protein and the G Protein-Gated K^+ Channel 317
2. Specificity of Signal Transduction Based on the Receptor/G Protein/G Protein-Gated K^+ Channel Interaction 317
D. Localization of the G Protein-Gated K^+ Channel Systems in Various Organs 318
I. Cardiac Atrial Myocytes 319
II. Neurons 321
III. Endocrine Cells 322
E. Weaver Mutant Mice and GIRK2 Gene 323
F. Conclusions 323
References 324
CHAPTER 13
Potassium Channels with Two Pore Domains
F. Lesage, M. Lazdunski. With 3 Figures 333
A. K^+ Channels with One Pore Domain 333
B. K^+ Channels with Two Pore Domains 334
I. TWIK, the Archetype of a Novel Structural Class of K^+ Channel 334
1. Cloning and Gene Organization 334
2. Functional Expression 335
3. Structure of the Channel 337
II. Related K^+ Channels in Mammals 337
1. TREK is an Unusual Outward Rectifier K^+ Channel 338
2. TASK is an Open Rectifier Channel Highly Sensitive to External pH 339
3. TRAAK Forms K^+ Channels Activated by Unsaturated Fatty Acids 340
III. Related Channels in Worm, Fly, Yeast, and Plant 340
C. Concluding Remarks 341
References 343
CHAPTER 14
Cardiac K^+ Channels and Inherited Long QT Syndrome
M.-D. Drici, J. Barhanin. With 3 Figures 347
A. Long QT Syndromes 347
B. HERG and LQT2 348
I. The HERG Gene 348
II. I_{Kr} Current and LQT2 348
C. KvLQT1/IsK, LQT1, and LQT5 352
I. KVLQT1 and ISK Genes 352
II. I_Ks Current, LQT1, and LQT5 352
III. Physiological Role of I_Ks in Cardiac Repolarization 355
D. Pharmacological Considerations in the Acquired LQTS 356
I. Determinants of Cardiac Repolarization 356
II. Pharmacological Modulation of Cardiac Repolarization and Acquired Long QT Syndromes 357
E. Conclusion 358
References 359
Section II: Ligand Operated Ion Channels
CHAPTER 15
Gating of Ion Channels by Transmitters: The Range of Structures of the Transmitter-Gated Channels
E.A. Barnard. With 4 Figures 365
A. Introduction: The Scope of the Transmitter-Gated Channel Class 365
B. Structural Elements of the Membrane Domains of the Transmitter-Gated Channels 366
I. Transmembrane Domains 366
II. The alpha-Helix in Channel Transmembrane Domains 367
III. Supporting Transmembrane Structures 371
IV. Pore Loops (P-Domains) 371
C. The Subclasses of the Transmitter-gated Channels 373
I. The TGCs are in Completely Diverse Superfamilies 373
II. The Cys-Loop Receptors 374
III. Glutamate-Gated Cation Channels 378
IV. Channels Structurally Related to Voltage-Gated Channels 379
1. Cyclic Nucleotide-Gated Channels 379
2. Inositol Trisphosphate (IP_3) Receptors 380
3. Ryanodine Receptors 380
4. Vanilloid Receptors and Store-Operated Channels 380
V. Channels Topologically Related to Epithelial Na^+ Channels 381
1. P2X Channels 381
2. Proton-Gated Channels 381
3. Peptide-Gated Channels 383
VI. Channels Related to Inward Rectifier K^+ Channels 383
1. Nucleotide-Sensitive K^+ Channels 383
2. Nucleotide-Dependent K^+ Channels 384
3. Channels Containing Bi-Functional Kir Subunits 384
VII. Channels Related to ATP-Binding Transporters 385
VIII. Channels Related to Neurotransmitter Transporters 385
D. Conclusion 386
References 386
CHAPTER 16
Molecular Diversity, Structure, and Function of Glutamate Receptor Channels
M. Mishina. With 2 Figures 393
A. Introduction 393
B. Structure and Molecular Diversity of the GluR Channel 393
I. Subunit Families and Subtypes 393
II. Primary Structure and Transmembrane Topology Model 394
C. AMPA Subtype 395
I. AMPA-Type Subunits 395
II. GluR2 Subunit and Ca^{2+} Permeability 396
III. Q/R Site as a Determinant of Channel Properties 396
IV. Phosphorylation 397
V. Autoimmune Disease 397
VI. GRIP, an Associated Protein 397
D. Kainate Subtype 397
E. NMDA Subtype 398
I. Heteromeric Nature of NMDA Receptor Channels 398
II. Dynamic Variations of the Distribution of the Subunits 399
III. Splice Variants 400
IV. Channel Pore and Gating 401
V. Agonist Binding 402
VI. Phosphorylation 403
VII. Modulation 403
VIII. Synaptic Plasticity, Learning, and Neural Development 404
IX. Associated PostSynaptic Proteins 404
F. Additional Members of the GluR Channel Family 405
I. GluRdelta Subfamily 405
II. GluRchi Subfamily 406
References 406
CHAPTER 17
Glutamate Receptor Ion Channels: Activators and Inhibitors
D.E. Jane, H.-W. Tse, D.A. Skifter, J.M. Christie, D.T. Monaghan. With 15 Figures 415
A. Introduction 415
I. Receptor Classification 415
II. Molecular Biology of AMPA, Kainate, and NMDA Receptors 416
B. Pharmacology of AMPA Receptors 417
I. AMPA Receptor Agonists 417
II. Competitive AMPA Receptor Antagonists 419
1. Quinoxalinediones and Related Compounds 419
2. Decahydroisoquinolines 423
3. Isoxazoles 425
4. Phenylglycine and Phenylalanine Analogues 426
III. Benzodiazepine Analogues as Non-Competitive AMPA Receptor Antagonists 427
IV. Positive Allosteric Modulators 428
V. Channel Blockers 429
C. Kainate Receptor Pharmacology 431
I. Kainate Receptor Agonists 431
II. Competitive Kainate Receptor Antagonists 433
1. Quinoxalinediones and Related Compounds 433
2. Decahydroisoquinolines 433
3. Positive Allosteric Modulators Acting on Kainate Receptors 434
D. Therapeutic Potential of AMPA and Kainate Receptor Ligands 434
E. Pharmacology of NMDA Receptors 436
I. Therapeutic Considerations 436
II. The NMDA Receptor Glutamate Recognition Site 438
1. Glutamate Recognition Site Radioligands 438
2. Glutamate Binding Site Agonists 439
3. Glutamate Recognition Site Competitive Antagonists 440
4. Antagonist Specificity for Subtypes of Glutamate Recognition Sites 443
III. NMDA Receptor Channel Blockers 444
1. Channel Blocker Pharmacology 444
2. Channel Blocker Receptor Subtype Selectivity 446
IV. The NMDA Receptor Glycine Recognition Site 447
1. Radioligand Binding and Functional Characteristics of the Glycine Receptor 447
2. NMDA Receptor Glycine Site Agonists 449
3. NMDA Receptor Glycine Site Antagonists 450
V. Allosteric Modulatory Sites on the NMDA Receptor 452
1. Polyamines 452
2. Spider and Wasp Toxins 453
3. Ifenprodil and Other NR2B Selective Compounds 453
4. Proton Inhibition 455
5. Zinc 455
F. Conclusions 456
References 459
CHAPTER 18
Structure, Diversity, Pharmacology, and Pathology of Glycine Receptor Chloride Channels
R.J. Harvey, H. Betz. With 2 Figures 479
A. Introduction 479
I. The Neurotransmitter Glycine 479
B. Structure and Diversity of Glycine Receptor Channels 479
I. GlyRs are Ligand-Gated Ion Channels of the nAChR Superfamily 479
II. Glycine Receptor Heterogeneity 480
III. The GlyR Ligand-Binding Domain 482
IV. Determinants of Ion Channel Function 483
V. Clustering of GlyRs by the Anchoring Protein Gephyrin 484
C. Pharmacology of Glycine Receptors 484
I. Strychnine is a Selective GlyR Antagonist 484
II. Amino Acids and Piperidine Carboxylic Acid Compounds 486
III. Antagonism by Picrotoxinin, Cyanotriphenylborate, and Quinolinic Acid Compounds 487
IV. Potentiation of GlyR Function by Anesthetics, Alcohol and Zn^{2+} 488
D. Pathology of Glycine Receptors 489
I. Mouse Glycine Receptor Mutants: Spastic, Spasmodic, and Oscillator 489
II. Mutations in GLRA1 Underlie the Human Hereditary Disorder Hyperekplexia 490
E. Conclusions 491
References 492
CHAPTER 19
GABA_A Receptor Chloride Ion Channels
R.W. Olsen, M. Gordey. With 4 Figures 499
A. GABAA Receptors: Physiological Function, Molecular Structure, Pharmacological Subtypes 499
B. Activators and Inhibitors of GABA_A Receptors 502
I. GABA Site 502
1. Agonists 502
2. Antagonists 504
II. The Picrotoxin Site 505
III. Benzodiazepine Site Ligands 506
IV. Barbiturates and Related Drugs 509
V. Neuroactive Steroids 511
VI. General Anesthetics: Propofol, Volatile Agents, and Alcohols 511
VII. Miscellaneous Agents 512
C. Discussion 512
References 512
CHAPTER 20
P2X Receptors for ATP: Classification, Distribution, and Function
R.J. Evans. With 1 Figure 519
A. Introduction 519
B. Molecular Biology of P2X Receptors 519
I. A New Structural Family of Ligand Gated Ion Channels 520
II. The Extracellular Loop/Ligand Binding Site 520
III. Transmembrane Domains; Location of the Ionic Pore 522
1. Intracellular N and C Termini 523
2. Genomic Organisation, Human P2X Receptors and Chromosomal Location 523
C. Distribution of P2X Receptors 523
I. P2X_1 Receptors 524
II. P2X_2 Receptors 524
III. P2X_3 Receptors 525
IV. P2X_4 Receptors 525
V. P2X_5 Receptors 526
VI. P2X_6 Receptors 526
VII. P2X_7 Receptors 526
D. Functional Properties of P2X Receptors 527
I. General Features of P2X Receptors 527
1. P2X_1 Receptors 528
2. P2X_2 Receptors 528
3. P2X_3 Receptors 529
4. P2X_2/P2X3 Heteromeric Receptors 529
5. P2X_4 Receptors 529
6. P2X_5 Receptors 530
7. P2X_6 Receptors 530
8. P2X_7 Receptors 530
II. Modulation of P2X Receptors 531
III. Native P2X Receptor Phenotypes; Molecular Correlates 532
1. Smooth Muscle 532
2. Sensory Neurons 533
3. Peripheral Neurons 534
4. Brain 534
5. Immune/Blood Cells 534
6. Salivary Gland 535
E. Future Directions 535
References 535
CHAPTER 21
The 5-HT_3 Receptor Channel: Function, Activation and Regulation
J.L. Yakel. With 1 Figure 541
A. Introduction 541
B. Receptor Distribution 542
C. Molecular Structure 542
I. Sequence, Assembly, and Splice Variants 542
II. Gene Structure 544
III. Developmental Regulation 544
IV. Homo-Oligomeric Vs Hetero-Oligomeric Assembly 544
D. Function in the Nervous System 545
I. Presynaptic Role and Neurotransmitter Release 545
II. Postsynaptic Role 546
III. Physiological Properties 547
1. Receptor Activation 547
2. Single-Channel Properties 547
3. Desensitization 548
4. Ion Permeation and Pore Structure 549
5. Rectification and Voltage-Dependence 550
IV. Modulation, Synaptic Plasticity, and Learning and Memory 551
E. Pharmacological Properties 552
I. 5-HT_3R Ligands: Agonists and Antagonists 552
II. 5-HT_3R Ligand Binding Site 553
F. Allosteric Regulation 554
I. Alcohols 554
II. Anesthetics 554
III. 5-Hydroxyindole 555
G. Conclusion 555
References 556
CHAPTER 22
Cyclic Nucleotide-Gated Channels: Classification, Structure and Function, Activators and Inhibitors
M.E. Grunwald, H. Zhong, K.-W. Yau. With 2 Figures 561
A. Introduction 561
B. Structure 562
C. Ion Permeation Properties 563
D. Cyclic-Nucleotide Binding and Channel Gating 565
E. Modulations 568
I. Ca^{2}-Calmodulin 568
II. Ca^{2} 569
III. Phosphorylation 569
IV. Transition Metals 570
V. Sulfhydryl Reagents 570
VI. Protons 571
VII. Other Modulators 571
F. Blockers 571
G. Conclusions 572
References 573
Section III: Miscellaneous Ion Channels  Intracellular Ca Release Channels
CHAPTER 23
Regulation of Ryanodine Receptor Calcium Release Channels
M. Endo, T. Ikemoto 583
A. Introduction 583
B. Molecular Structure and Function of RyR 584
C. Different Modes of Opening of RyR1 Calcium Release Channel 585
D. Activators of RyRs 588
I. Calcium, Strontium, and Barium Ions 589
II. Adenine Compounds 590
III. Caffeine and Related Compounds 590
IV. Ryanodine and Ryanoid 591
V. Halothane and Other Inhalation Anesthetics 592
VI. Oxidizing Agents and Doxorubicin 593
VII. Cyclic ADP-Ribose 593
VIII. Calmodulin and Other Endogenous Modulatory Proteins 593
IX. Imperatoxin Activator 594
X. Clofibric Acid 594
XI. Miscellaneous Activators 595
E. Inhibitors of RyRs 595
I. Magnesium Ion 595
II. Procaine and Other Local Anesthetics 596
III. Ruthenium Red 596
IV. Dantrolene 596
F. Closing Remarks 596
References 597
CHAPTER 24
Regulation of IP_3 Receptor Ca^{2+} Release Channels
M. Iino. With 1 Figure 605
A. Introduction 605
B. Molecular Structure and Function of IP_3R 605
C. Physiological Agonists and Modulators of IP_3R 607
I. IP_3 607
II. Ca^{2+} 609
III. ATP 610
IV. Phosphorylation 610
D. Activators of IP_3R 611
I. IP_3 Analogues 611
II. Caged IP_3 612
III. Thimerosal 612
IV. Immunophilin Ligands 613
V. Mn^{2+} 613
E. Inhibitors of IP_3R 613
I. Heparin 613
II. Xestospongin 614
III. Caffeine 614
IV. Cyclic ADP-Ribose 614
F. Comparison of Pharmacology Between IP_3R and RyR 615
G. Spatio-Temporal Patterns of IP_3R-Mediated Ca^{2+} Signals 615
H. Perspectives 617
References 617
CHAPTER 25
Ca^{2+}-Activated Non-Selective Cation Channels
J. Teulon 625
A. Introduction 625
B. Tissue Distribution 625
C. Conductive Properties 628
I. Unit Conductance and Voltage Dependence 628
II. Ion Selectivity 629
III. Ca-Permeable, Ca-Dependent Cation Channels: A Subtype of theNSC_{Ca} Channel? 630
D. Blockers and Pharmacological Stimulators 630
I. Blockers 630
II. Pharmacological Stimulators 632
E. Intracellular Regulatory Elements 633
I. Calcium Sensitivity 633
II. Inhibition by Intracellular Nucleotides 633
III. Tonic Influence of Intracellular ATP 635
IV. Stimulatory Effects of Intracellular Cyclic Nucleotides 635
V. Other Regulators: Internal pH and Oxidation 635
F. Phosphorylation-Dependent Regulation 636
I. Regulation via Protein Kinase A 636
II. Effects of Other Protein Kinases 637
G. Dependence on Hypertonicity 637
H. Agonist-Mediated Control of NSC_{Ca} Channels 638
I. Physiological Role 639
I. Excitable Cells: "Voltage Signal" 640 
II. Exocrine Glands: Participation in Cl^- Transport 641
III. Other Epithelia: Speculative Functions 642
References 643
Subject Index 651
END
