Secretory Systems and Toxins (Cellular and molecular mechanisms of toxin action)

BOOK COVER......Page 1
HALF-TITLE......Page 2
TITLE......Page 4
COPYRIGHT......Page 5
CONTENTS......Page 6
PREFACE TO THE SERIES......Page 8
PREFACE......Page 10
CONTRIBUTORS......Page 13
SECRETION AS A UNIFYING THEME......Page 18
The SNARE Hypothesis......Page 19
NSF and SNAP......Page 21
VAMP/synaptobrevin......Page 22
SNAP-25......Page 25
Syntaxin......Page 27
Synaptophysin/Synaptoporin......Page 29
Synaptotagmin/p65......Page 33
nSec1/rbSec1/Munc-18......Page 38
Rab3a......Page 39
Rabphilin3A......Page 40
Synapsin......Page 41
Cysteine String Protein......Page 43
Proton Pump......Page 44
Neurotransmitter Transporters......Page 45
Dynamin......Page 46
CONCLUDING REMARKS......Page 47
REFERENCES......Page 48
INTRODUCTION......Page 62
GENE KNOCKOUTS IN MICE—THE PROS AND CONS......Page 63
Synaptotagmin I......Page 65
Synapsin I and II......Page 67
Synaptophysin I......Page 68
Rab 3A......Page 69
Synaptobrevin......Page 70
Cysteine String Protein (CSP)......Page 71
unc-18......Page 72
Dynamin......Page 73
REFERENCES......Page 74
INTRODUCTION......Page 81
Neurotransmitter Release: A Paradigm of Vesicle Mediated Membrane Traffic......Page 82
Targetting Exocytosis: A Heavy Chain of Events......Page 84
Cleavage of Essential Exocytotic Proteins: The Light Side of Toxins......Page 86
IN VITRO INTERACTIONS INVOLVING THE DEFINED SUBSTRATES OF THE CLOSTRIDIAL TOXINS......Page 87
Cellular and Sub-Cellular Investigations......Page 89
Protein Interaction Studies......Page 91
Clostridial Neurotoxins and Ca2+-dependent Reactions: Clues to the Physiological Regulation of Transmitter Release......Page 92
PERSPECTIVES......Page 94
REFERENCES......Page 95
INTRODUCTION......Page 100
Overview......Page 101
Vesicle Biogenesis: Role of Coat Proteins......Page 102
Vesicle Biogenesis: Role of Phospholipid Metabolism......Page 106
Vesicle Transport and Docking: The Cytoskeleton and a Triple-Sec Exocytic Particle......Page 109
Vesicle Docking and Fusion: SNARE Complex Formation......Page 111
Vesicle Docking and Fusion: Regulation of SNARE Activation......Page 114
Vesicle Docking and Fusion: Rab Proteins in Secretion......Page 116
Parallel Exocytic Pathways: A Model for Higher Eukaryotes?......Page 117
Yeast as a Model System for Studying Neurotoxin Function......Page 119
CONCLUSIONS: YEAST AS A SECRETORY DELPHIC ORACLE?......Page 120
REFERENCES......Page 121
INTRODUCTION......Page 130
Phospholipid-Metabolizing Enzymes Implicated in Membrane Traffic......Page 131
How Might Phospholipids Regulate Membrane Traffic Events?......Page 134
THE ROLES OF SPHINGOLIPIDS IN REGULATING MEMBRANE TRAFFIC......Page 136
REFERENCES......Page 144
PROTEINS IMPLICATED IN FUSION......Page 153
THE TARGET MEMBRANE OF FUSION......Page 155
PROPERTIES OF THE INITIAL FUSION PORE......Page 158
IS THE FUSION PORE FORMED BY SYNAPTOPHYSIN RELATED PROTEINS?......Page 161
TRANSIENT OPENING OF FUSION PORES......Page 162
TRANSMITTER RELEASE THROUGH SMALL AND TRANSIENT FUSION PORES......Page 163
ACKNOWLEDGEMENT......Page 164
REFERENCES......Page 165
CELL RECOGNITION AND MEMBRANE BINDING......Page 169
INTRODUCTION......Page 170
POLYSIALOGANGLIOSIDES STRUCTURE AND TETANUS TOXIN RECOGNITION......Page 171
THE ROLE OF POLYSIALOGANGLIOSIDES IN TETANUS TOXIN BINDING TO NEURONS......Page 175
POLYSIALOGANGLIOSIDES, NEURAL FUNCTIONS AND SIGNAL TRANSDUCTION......Page 179
GANGLIOSIDE-MEDIATED EFFECTS OF TETANUS TOXIN ON NEURONAL SIGNAL TRANSDUCTION......Page 181
CONCLUSIONS......Page 185
REFERENCES......Page 186
INTRODUCTION......Page 195
INTERACTION OF NEUROTOXIN WITH GANGLIOSIDES......Page 196
CHARACTERIZATION OF BOTULINUM NEUROTOXIN RECEPTOR......Page 197
IDENTIFICATION OF A PROTEIN RECEPTOR FOR TYPE B NEUROTOXIN......Page 198
SIGNIFICANCE OF SYNAPTOTAGMIN AS A RECEPTOR COMPONENT FOR BOTULINUM NEUROTOXIN......Page 200
INTERACTION OF NEUROTOXIN WITH PHOSPHOLIPIDS......Page 202
REFERENCES......Page 203
INTRODUCTION......Page 207
NEUROTOXIC EFFECTS OF a-LATROTOXIN......Page 208
BIOCHEMICAL CHARACTERIZATION AND PURIFICATION OF a-LATROTOXIN RECEPTORS......Page 211
NEUREXINS AND NEUREXIN-BINDING PROTEINS......Page 215
CALCIUM-INDEPENDENT a-LATROTOXIN RECEPTOR (CIRL)......Page 218
a-LATROTOXIN RECEPTORS—SUBCELLULAR DISTRIBUTION......Page 220
a-LATROTOXIN RECEPTORS AND THE MECHANISM OF a-LATROTOXIN ACTION......Page 223
REFERENCES......Page 228
TOXIN’S MODE OF ACTION......Page 236
INTRODUCTION......Page 237
CONSTITUTIVE VS. REGULATED SECRETION......Page 238
Ca2+-DEPENDENT REGULATED SECRETION......Page 239
DISCRETE STEPS OF RELEASE......Page 240
VOLTAGE DEPENDENT Ca2+ CHANNELS IN NERVE TERMINALS......Page 241
Ca2+ SENSORS IN THE NERVE TERMINALS......Page 243
ADDITIONAL SAFETY-LATCHES IN NEUROTRANSMITTER RELEASE......Page 244
Slow Release Systems......Page 245
TOWARDS A MOLECULAR DESCRIPTION OF RELEASE INITIATION......Page 246
a-LATROTOXIN AND ITS MULTIPLE MODES OF ACTION......Page 247
a-LATROTOXIN AND ITS Ca2+-DEPENDENT MODE OF ACTION......Page 248
a-LATROTOXIN AND ITS Ca2+-INDEPENDENT MODE OF ACTION......Page 249
POSSIBLE ADDITIONAL MODES OF ACTION OF a-LATROTOXIN......Page 251
REFERENCES......Page 254
BOTULISM AND TETANUS......Page 268
WHY USE APLYSIA TO STUDY THE MOLECULAR BASIS OF BOTULISM AND TETANUS?......Page 269
BoNTs and TeNT Block Synaptic Vesicle Exocytosis......Page 270
Differences in the Blocking Action of BoNTs and TeNT......Page 272
Light Chain Needs to be Free in the Cytosol to be Active......Page 273
The Three Steps Model......Page 274
H Chain Mediates Neuroselective Binding......Page 275
Binding at Peripheral and Central Synapses, a Working Hypothesis......Page 276
Internalization and Translocation......Page 278
THE METALLO-ENDOPEPTIDASE HYPOTHESIS......Page 279
Cleavage of the Neurotoxin Targets and Inhibition of Neurotransmission......Page 280
Protection Against the Toxins is Afforded by the Formation of a Complex Comprising their Targets......Page 281
Does the Target Fragment Released by the Neurotoxins Contribute to the Inhibitory Action?......Page 283
Evidence for a Non-proteolytic Inhibitory Action......Page 284
Transglutaminases are Involved in TeNT Action......Page 285
A Working Hypothesis......Page 286
REFERENCES......Page 287
INTRODUCTION......Page 296
PROTEINS PARTICIPATING IN EXOCYTOSIS IDENTIFIED WITH NEUROTOXINS......Page 297
ADDITIONAL VESICULAR PROTEINS INVOLVED IN EXOCYTOSIS......Page 300
INTERACTIONS OF PROTEINS OF THE EXOCYTOSIS APPARATUS......Page 301
REFERENCES......Page 302
BINDING OF a-LTX TO THE PLASMA MEMBRANE......Page 311
a-LTX STIMULATED ION FLUXES......Page 312
a-LTX STIMULATED NEUROTRANSMITTER RELEASE......Page 313
REFERENCES......Page 316
STRUCTURE AND FUNCTION—TOXINS AND THEIR TARGETS......Page 323
14. BOTULINUM NEUROTOXINS AND THEIR SUBSTRATES......Page 324
Molecular Structure......Page 325
Protein-protein Interactions and Proposed Functions......Page 326
Isoforms and Homologs......Page 327
Protein-protein Interactions and Proposed Function......Page 328
General Aspects......Page 329
Isoforms and Homologs......Page 330
Protein-protein Interactions and Proposed Functions......Page 331
REFERENCES......Page 333
INTRODUCTION......Page 341
STRUCTURE OF CLOSTRIDIAL NEUROTOXINS......Page 342
BINDING TO NEURONS......Page 345
Toxin Internalization and Membrane Translocation into the Cytosol......Page 346
The Metalloproteinase Activity of Tetanus and Botulinum Neurotoxins......Page 347
Clostridial Neurotoxins and the Blockade of Neurotransmitter Release......Page 351
ACKNOWLEDGMENTS......Page 352
REFERENCES......Page 353
INTRODUCTION......Page 359
Latrodectus and Latrodectism......Page 360
Experiments with Venom Gland Extracts......Page 361
Historical Developments......Page 362
Purification Procedure......Page 363
Properties of a-Latrotoxin and Definition of Problems......Page 365
Molecular Structure of a-Latrotoxin......Page 369
Membrane Binding and Targeting......Page 371
Selectivity of a-Latrotoxin Action......Page 373
DISCUSSION......Page 375
ACKNOWLEDGEMENTS......Page 377
REFERENCES......Page 378
TOXINS AS PROBES OF CELL PHYSIOLOGY......Page 383
INTRODUCTION......Page 384
SYNAPSE FORMED BETWEEN SCGNS IN CULTURE......Page 385
Electrophysiological Recording of Synaptic Responses......Page 386
Microinjection Procedures......Page 387
a-Latrotoxin Responses......Page 389
INVOLVEMENT OF MYOSIN II IN TRANSMITTER SECRETION AT THE SCGN SYNAPTIC TERMINAL......Page 390
Functional Block of Myosin II Activity......Page 392
Inhibition of MLCK Activity......Page 393
Summary......Page 395
INTERACTION OF SYNTAXIN AND CALCIUM CHANNELS AT THE SCGN SYNAPTIC TERMINAL......Page 396
N-type Ca2+ Channels Mediate Transmitter Secretion......Page 397
Functional Block of Syntaxin......Page 398
Inhibition of Transmitter Secretion by N-type Ca2+ Channel Fusion Proteins......Page 399
Prolongation of Transmitter Secretion in Response to Repetitive Stimuli......Page 401
CONCLUSIONS......Page 403
REFERENCES......Page 405
INTRODUCTION......Page 412
STRUCTURE OF THE SYNAPSIN GENES AND PROTEINS......Page 413
BIOCHEMICAL AND BIOPHYSICAL PROPERTIES......Page 417
CELLULAR AND SUBCELLULAR DISTRIBUTION......Page 419
INTERACTIONS WITH SYNAPTIC VESICLES......Page 421
INTERACTIONS WITH THE ACTIN-BASED CYTOSKELETON......Page 423
INTERACTIONS WITH OTHER CYTOSKELETAL COMPONENTS......Page 425
REGULATION BY PHOSPHORYLATION......Page 426
WORKING MODELS FOR SYNAPSIN I FUNCTION IN THE MATURE NERVE TERMINAL......Page 429
EVIDENCE FOR A ROLE IN THE REGULATION OF NEUROTRANSMITTER RELEASE......Page 430
SYNAPSIN EXPRESSION DURING NEURONAL DEVELOPMENT......Page 433
AXONAL TRANSPORT......Page 434
EVIDENCE FOR A ROLE IN THE REGULATION OF NEURONAL DEVELOPMENT AND SYNAPTOGENESIS......Page 435
CONCLUSIONS......Page 436
REFERENCES......Page 437
CLOSTRIDIAL TOXINS......Page 445
Morphological Studies of Neurotransmitter Release Employing Clostridial Toxins......Page 446
a-LATROTOXIN......Page 449
Morphological Studies of Neurotransmitter Release Employing a-LTx......Page 451
w-CONOTOXINS AND w-AGATOXINS......Page 454
Morphological Studies of Calcium Channels Controlling Neurotransmitter Release Using w-conotoxins and w-agatoxins......Page 456
REFERENCES......Page 460
GTP AND Ca2+ ARE REGULATORS OF EXOCYTOSIS......Page 466
Ca2+ AND GTP ACT COINCIDENTLY AND CLOSE TO THE EXOCYTOTIC FUSION SITE.......Page 467
EVIDENCE FOR ANNEXIN VII AS A MEDIATOR OF GTP AND Ca2+ ACTIVATION OF EXOCYTOTIC MEMBRANE FUSION......Page 468
MASTOPARAN ACTIVATION OF SYNEXIN GTPASE......Page 469
CYCLIC SYNEXIN SWITCH FOR MEMBRANE FUSION......Page 471
CONCLUSIONS......Page 473
REFERENCES......Page 474
GLOSSORY......Page 477
INDEX......Page 495