Cholinergic mechanisms : function and dysfunction

The cholinergic synapse is an important interdisciplinary research topic. In the first place, it stands as a useful system for investigating many fundamental issues of development, structure and function/malfunction of synapses in general. Also, its crucial biological role makes it the target of a variety of natural toxins and synthetic poisons and drugs. For example, it is the target of the first generation of anti-Alzheimer drugs, of nerve agents and insecticides, of botulinum toxin and the South American Indian arrow poison, curare, and of drugs for the treatment of myasthenia gravis and glaucoma. It is therefore not surprising to find many neuroscientists, with a broad range of interests, focusing their research on this synapse. The triennnial symposium on cholinergic mechanisms provides a key multidisciplinary forum for their interaction, and the proceedings, compiled in this volume, of the Eleventh ISCM, held in St. Moritz in May 2002, provide a cutting edge profile of research progress in this important field of study. Cover......Page 1 Cholinergic Mechanisms: Function and Dysfunction......Page 2 Contents......Page 4 Preface......Page 20 Contributors......Page 22 SCIENTIFIC CAREER......Page 78 RESEARCH, 1968–1974......Page 79 THE FIRST ISCM......Page 80 PERSONAL RECOLLECTIONS......Page 81 REFERENCES......Page 82 FUNCTION......Page 84 ACh-BINDING SITES......Page 85 STRUCTURE OF THE MEMBRANE DOMAIN......Page 86 CHANNEL DYNAMICS......Page 87 RESTING-STATE GATE......Page 89 DESENSITIZED-STATE GATE......Page 90 REFERENCES......Page 91 THE BINDING SITE IN ANIMAL SPECIES THAT ARE RESISTANT TO α-BTX......Page 96 A LEAD PEPTIDE SELECTED BY α-BTX FROM A RANDOM PHAGE-DISPLAY PEPTIDE LIBRARY......Page 97 HAPs DESIGNED BY SYSTEMATIC RESIDUE REPLACEMENT......Page 98 THE NMR STRUCTURE OF A HAP/α-BTX COMPLEX IN SOLUTION......Page 99 THE CRYSTAL STRUCTURE OF A HAP/α-BTX COMPLEX......Page 100 CONCLUDING REMARKS......Page 101 REFERENCES......Page 102 INTRODUCTION......Page 104 IDENTIFICATION OF THE SITES BY WHICH VARIOUS SNAKE TOXINS INTERACT WITH DIFFERENT NICOTINIC ACHR SUBTYPES......Page 105 DETERMINATION OF THE α7 RECEPTOR RESIDUES INVOLVED IN THE α-Cbtx INTERACTION AND IDENTIFICATION OF TOXIN-RECEPTOR INTERACTING RESIDUES BY CYCLE-MUTANT EXPERIMENTS......Page 106 STRUCTURAL MODEL OF THE α-Cbtx-α7 NEURONAL NICOTINIC AChR COMPLEX......Page 107 REFERENCES......Page 108 LIPID SITES AT THE AChR MEMBRANE INTERFACE......Page 110 SECONDARY STRUCTURE OF AChR TM DOMAINS......Page 112 REFERENCES......Page 114 STUDIES AND RESULTS......Page 116 CONCLUSIONS......Page 120 REFERENCES......Page 121 INTRODUCTION......Page 122 STRUCTURE OF THE BOUND α-BTX......Page 123 STRUCTURE OF THE BOUND α1182–202......Page 124 MODELING OF THE AChR-EC/α-BTX COMPLEX......Page 125 LIGAND-BINDING SITE OF AChR......Page 126 BR36 OCCUPIES ACETYLCHOLINE-BINDING POCKET......Page 127 BR36 IS INVARIANT IN SNAKE α-NEUROTOXINS......Page 128 NMR STRUCTURE OF THE α-BTX COMPLEXED WITH α1182–202 ACCOUNTS FOR SPECIES-SPECIFIC SUSCEPTIBILITY TO THE TOXIN......Page 129 REFERENCES......Page 130 USE OF SCANNING MUTAGENESIS TO PROBE THE FUNCTIONS OF AMINO ACIDS IN RECEPTOR SEQUENCES......Page 132 A HOMOLOGY MODEL OF THE M1 MUSCARINIC RECEPTOR......Page 133 THE BINDING SITE FOR ACETYLCHOLINE AND N-METHYL SCOPOLAMINE......Page 134 A LIGAND DOCKING SITE?......Page 135 INTRAMOLECULAR CONTACTS THAT SELECTIVELY STABILIZE THE GROUND STATE......Page 136 TRANSDUCTION OF ACh-BINDING ENERGY INTO RECEPTOR ACTIVATION......Page 137 REFERENCES......Page 138 M1R−/− MICE ARE HYPERACTIVE......Page 140 M2 AND M4 RECEPTORS MEDIATE MUSCARINIC AGONIST-INDUCED ANALGESIC EFFECTS AT SPINAL AND SUPRASPINAL SITES......Page 141 M2 RECEPTORS MEDIATE MUSCARINIC AGONIST-INDUCED DESENSITIZATION OF PERIPHERAL NOCICEPTORS......Page 142 CENTRAL MUSCARINIC AUTORECEPTORS......Page 143 M5 RECEPTORS MEDIATE ACh-INDUCED DILATION OF CEREBRAL ARTERIES AND ARTERIOLES......Page 144 REFERENCES......Page 145 INTRODUCTION......Page 148 ALLOSTERIC PROPERTIES OF MUSCARINIC RECEPTORS......Page 149 INFLUENCE OF MODIFICATIONS IN o2 AND o3 OF M3 RECEPTOR ON ALLOSTERIC CHARACTERISTICS......Page 150 IMPLICATIONS......Page 151 REFERENCES......Page 152 11. René Couteaux (1909–1999) and his presynaptic active zone......Page 154 REFERENCES......Page 156 A STRUCTURE AT MOLECULAR LEVEL RESOLUTION—NICOTINIC RECEPTORS FROM MUSCLE......Page 158 ACETYLCHOLINE-BINDING PROTEIN A SURROGATE FOR THE PENTAMERIC LIGAND-GATED ION CHANNEL......Page 160 ACETYLCHOLINESTERASE—EXTENDING BEYOND STATIC STRUCTURAL TEMPLATES......Page 161 REFERENCES......Page 163 13. Neuronal calcium dynamics: one message with many meanings......Page 164 REFERENCES......Page 167 THE CHOLINERGIC MEDIATOPHORE IS ABLE TO RELEASE GLUTAMATE AS WELL......Page 168 A GLUTAMATERGIC MEDIATOPHORE?......Page 169 TWO CHOICES FOR THE SAME FUNCTION......Page 170 AN UNSUSPECTED DIFFERENCE BETWEEN CHOLINERGIC AND GLUTAMATERGIC SYNAPTOSOMES......Page 171 MEDIATOPHORE IN CHOLINERGIC AND GLUTAMATERGIC BRAIN AREAS......Page 172 POSSIBLE PATHOLOGICAL IMPLICATIONS OF ACh AND GLU CO-RELEASE......Page 173 REFERENCES......Page 174 MOLECULAR EMBODIMENT OF THE Ca-VOLTAGE HYPOTHESIS......Page 176 IN KNOCKOUT MICE LACKING FUNCTIONAL M2R THE TIME-COURSE OF RELEASE IS SENSITIVE TO THE LEVEL AND KINETICS OF [Ca2+]i......Page 177 DISCUSSION......Page 179 REFERENCES......Page 180 INTRODUCTION......Page 182 ATP INDUCES INOSITOL PHOSPHATES AND INTRACELLULAR CA2+ MOBILIZATION IN MUSCLE......Page 183 FUNCTIONAL ROLE OF P2Y1 RECEPTOR IN DIRECTING THE POSTSYNAPTIC GENE EXPRESSION......Page 184 REFERENCES......Page 187 CULTURED HUMAN MUSCLE......Page 190 EXPRESSION OF AChR......Page 192 CONTROL OF FUNCTIONAL NMJ MATURATION IN THE IN VITRO INNERVATED HUMAN MUSCLE: THE ROLE OF AGRIN......Page 193 REFERENCES......Page 194 CHOLINERGIC ALLOSTASIS UNDER STRESS......Page 196 ACHE ALTERNATIVE SPLICING UNDER STRESS......Page 197 AChE-R: THE PRODUCT OF STRESS RESPONSES......Page 198 BIOMEDICAL IMPLICATIONS......Page 199 REFERENCES......Page 200 INDEPENDENT TRANSCRIPTION OF ChAT AND VAChT......Page 202 CIS-ACTIVE CGL ELEMENTS REQUIRED FOR CHOLINERGIC CELL-SPECIFIC EXPRESSION......Page 203 CHOLINERGIC AND NORADRENERGIC PHENOTYPES IN SYMPATHETIC NEURONS AND SWEAT GLANDS......Page 205 CO-EXPRESSION OF THE HIGH-AFFINITY CHOLINE TRANSPORTER WITH THE CGL MEMBERS......Page 206 REFERENCES......Page 207 RESULTS......Page 210 REFERENCES......Page 213 NEURONAL PHENOTYPE COMPLEXITY......Page 214 THE MODEL: P19 EMBRYONIC CARCINOMA CELLS......Page 215 TRANSCRIPTIONAL REGULATORS......Page 217 GENOMICS APPROACH......Page 218 FUTURE PERSPECTIVES......Page 219 REFERENCES......Page 220 22. Miriam M Salpeter (Mika)—biographical notes......Page 222 INTRODUCTION......Page 224 INPUT PARAMETERS AND SCALING ARGUMENTS FOR THE SIMULATION OF MINIATURE POSTSYNAPTIC CURRENTS......Page 225 RESULTS FROM THE TWO CATALOGS AND A SENSITIVITY STUDY......Page 226 AN ASYMMETRY BETWEEN DENERVATION AND REINNERVATION FOR THE NMJ......Page 227 AN INTERMEDIATE RECEPTOR TYPE INSERTED DURING REINNERVATION......Page 228 REFERENCES......Page 230 INTRODUCTION......Page 232 THE SPLICE VARIANTS OF AChE......Page 233 CHOLINESTERASE SUBUNITS OF TYPE T: THE STRUCTURE OF THE T PEPTIDE......Page 235 STRUCTURE OF THE WAT/PRAD COMPLEX......Page 237 CONCLUSION......Page 238 REFERENCES......Page 239 STRUCTURE OF NATIVE hBChE......Page 242 STRUCTURE OF AGED hBChE......Page 243 REFERENCES......Page 245 RESULTS AND DISCUSSION......Page 248 REFERENCES......Page 252 INTRODUCTION......Page 254 STRUCTURAL DETERMINANTS OF E2020 SELECTIVITY FOR HUMAN AChE VS HUMAN BChE......Page 255 CONTRIBUTION OF FUNCTIONAL CHARACTERIZATION OF HUMAN AChE-LIGAND COMPLEXES BY SITE-DIRECTED MUTAGENESIS TO STRUCTURE-BASED DRUG DESIGN......Page 256 REFERENCES......Page 258 RESULTS AND DISCUSSION......Page 260 REFERENCES......Page 263 STRUCTURE OF ace GENES AND THE ENCODED PROTEINS......Page 264 CONCLUSIONS......Page 267 REFERENCES......Page 268 IDENTIFICATION OF DROSOPHILA CHOLINERGIC TRANSCRIPTIONAL REGULATORS......Page 270 INTRODUCTION OF Gal4 SYSTEM FOR STUDYING CHOLINERGIC LOCUS REGULATION......Page 271 WHAT OTHER GENES ARE EXPRESSED IN CHOLINERGIC NEURONS?......Page 272 REFERENCES......Page 274 THE nAChR GENE FAMILY OF CAENORHABDITIS ELEGANS......Page 276 THE nAChR GENE FAMILY OF DROSOPHILA MELANOGASTER......Page 279 REFERENCES......Page 281 DEG-3 IS A NONESSENTIAL GENE......Page 284 THE DEG-3/DES-2 CHANNEL......Page 285 RIC-3 IS NEEDED FOR MATURATION OF nAChRs......Page 286 RIC-3 IS A MEMBER OF A FUNCTIONALLY CONSERVED FAMILY OF PROTEINS......Page 287 OTHER GENES NEEDED FOR DEG-3 FUNCTION......Page 288 REFERENCES......Page 289 INTRODUCTION......Page 290 ENDPLATE CHOLINE ACETYLTRANSFERASE DEFICIENCY......Page 291 ENDPLATE ACETYLCHOLINESTERASE DEFICIENCY......Page 292 KINETIC MUTATIONS OF THE AChR......Page 294 SLOW-CHANNEL SYNDROMES......Page 295 FAST-CHANNEL SYNDROMES......Page 296 AChR DEFICIENCY CAUSED BY MUTATIONS IN AChR SUBUNIT GENES......Page 298 MYASTHENIC SYNDROME CAUSED BY MUTATIONS IN RAPSYN......Page 300 REFERENCES......Page 301 ARTHROGRYPOSIS MULTIPLEX CONGENITA (AMC)......Page 304 ‘SERONEGATIVE’ MG (SNMG)......Page 306 REFERENCES......Page 307 INTRODUCTION......Page 310 MUSCARINIC RECEPTOR AUTOANTIBODIES IN SJÖGREN’S SYNDROME INHIBIT PARASYMPATHETIC NEUROTRANSMISSION......Page 311 LOWER URINARY TRACT SYMPTOMS ARE INCREASED IN PRIMARY SJÖGREN’S SYNDROME......Page 312 DO MUSCARINIC RECEPTOR AUTOANTIBODIES IN SJÖGREN’S SYNDROME TARGET CARDIAC TISSUES?......Page 314 SUMMARY......Page 315 REFERENCES......Page 316 INTRODUCTION......Page 318 2. SUPPRESSION OF ONGOING EAMG BY A SYNGENEIC AChR RECOMBINANT FRAGMENT......Page 319 3. EFFECT OF DIRECT MODULATION OF KEY CYTOKINES AND CO-STIMULATORY FACTORS ON THE COURSE OF EAMG......Page 320 REFERENCES......Page 321 CHARACTERIZATION OF THE N-GLYCAN STRUCTURES ASSOCIATED WITH RECOMBINANT AND NATIVE BOVINE AChE......Page 322 EFFECT OF ENZYME TETRAMERIZATION ON THE PHARMACOKINETICS OF rBoAChE......Page 323 HUMAN AChE PHARMACOKINETICS ABIDES BY THE SAME POST-TRANSLATION-RELATED RULES AS BOVINE AChE......Page 325 HuAChE PHARMACOKINETICS IS AFFECTED BY THE NUMBER OF APPENDED N-GLYCANS......Page 328 REFERENCES......Page 329 CHEMICALS......Page 332 MICRODIALYSIS PROCEDURES......Page 333 THERAPEUTIC EFFICACY OF CPA IN OP POISONING......Page 334 CENTRAL ACh RELEASE DURING SARIN OR VX POISONING......Page 335 EFFECT OF PARTIAL A1 AGONISTS ON SARIN-INDUCED EPILEPTIFORM ACTIVITY......Page 336 THERAPEUTIC EFFICACY OF 2DCPA DURING SARIN POISONING......Page 337 THERAPEUTIC EFFICACY OF PARTIAL AGONISTS IN OP POISONING......Page 338 REFERENCES......Page 339 BIOSENSOR SYNTHESIS AND ASSAY......Page 342 COMPARISON OF SOLUBLE AND IMMOBILIZED ENZYMES......Page 343 LONGEVITY OF BIOSENSOR IN AQUEOUS ENVIRONMENTS......Page 344 DIFFERENTIAL DETECTION OF CHEMICAL WARFARE AGENTS......Page 345 CONCLUSIONS......Page 346 REFERENCES......Page 347 MATERIALS AND METHODS......Page 348 RESULTS......Page 349 DISCUSSION......Page 350 REFERENCES......Page 351 INTRODUCTION......Page 354 LIPOPHILICITY......Page 355 PERIPHERAL ANTI-INFLAMMATORY ACTIVITY......Page 356 RATIONALE OF DEVELOPMENT AND SYNTHESIS OF BIFUNCTIONAL COMPOUNDS......Page 357 INHIBITION KINETICS OF AChE AND BChE......Page 358 LIPOPHILICITY......Page 360 INHIBITION OF CYCLOOXYGENASE ISOENZYMES IN VITRO......Page 361 ANTI-INFLAMMATORY ACTIVITY IN BRAIN......Page 362 PROTECTION AGAINST CLOSED HEAD INJURY (CHI)......Page 363 REFERENCES......Page 364 42. In memoriam: Miroslav Brzin (13 April 1923–8 August 1999)......Page 366 AChE ACCUMULATION IN THE NEUROMUSCULAR JUNCTION......Page 368 MUSCLE FUNCTION INFLUENCES AChE EXPRESSION IN MUSCLES......Page 371 REFERENCES......Page 372 INTRODUCTION......Page 374 POTENTIATION BY GALANTAMINE OF ACh-INDUCED RESPONSES IN HEK293 CELLS STABLY EXPRESSING DIFFERENT nAChR SUBTYPES......Page 375 GALANTAMINE, ACTING AS A NICOTINIC APL, FACILITATES GLUTAMATERGIC TRANSMISSION IN RAT HIPPOCAMPAL SLICES......Page 376 ChE INHIBITION DOES NOT CONTRIBUTE TO THE POTENTIATING EFFECTS OF GALANTAMINE ON SYNAPTIC TRANSMISSION IN THE MAMMALIAN BRAIN......Page 379 WHY ChE INHIBITION PER SE DOES NOT INCREASE THE ACTIVITY OF ALL nAChRs IN THE BRAIN33 CHOLINE AS A FULL AGONIST AT α7 nAChRs......Page 380 SUMMARY AND DISCUSSION......Page 381 REFERENCES......Page 383 INTRODUCTION......Page 386 PSAB-OFP: A COMMON AGONIST OF 5-HT3Rs AND α7 nAChRs......Page 387 CONCLUSION......Page 390 REFERENCES......Page 391 INTRODUCTION......Page 394 KNOCKOUT MICE LACKING β2 AND/OR β4 SUBUNITS......Page 395 ANTONOMIC FUNCTION OF NEURONAL nAChR SUBUNITS......Page 396 REFERENCES......Page 398 INVOLVEMENT OF THE SEPTOHIPPOCAMPAL ACh SYSTEM IN EYEBLINK CONDITIONING......Page 400 SEPTOHIPPOCAMPAL ACh SYSTEM AND HUMAN NEUROPATHOLOGY......Page 401 GALANTAMINE AND ALLOSTERIC MODULATION......Page 402 GALANTAMINE AND EYEBLINK CLASSICAL CONDITIONING......Page 403 SUMMARY AND CONCLUSIONS......Page 404 REFERENCES......Page 405 DISTRIBUTION OF MUSCARINIC RECEPTOR SUBTYPES......Page 408 SYMPTOMS OF SCHIZOPHRENIA AND ASSOCIATED BRAIN REGIONS......Page 409 POST MORTEM ANALYSIS AND IN VIVO IMAGING OF MUSCARINIC RECEPTORS......Page 410 STUDIES IN ANIMALS IMPLICATING ROLE OF MUSCARINIC RECEPTORS IN SCHIZOPHRENIA......Page 411 DOPAMINE AND ACh RELEASE......Page 412 ELECTROPHYSIOLOGY......Page 413 COGNITION......Page 414 CLINICAL STUDIES WITH MUSCARINIC AGONISTS IN SCHIZOPHRENIA......Page 415 CONCLUSION......Page 416 REFERENCES......Page 417 THE M1 mAChR AS A THERAPEUTIC TARGET IN AD......Page 422 MODULATION OF Aβ LEVELS VIA M1 mAChR AND COMPARISON WITH SOME OTHER TREATMENTS......Page 424 PREVENTION OF Aβ NEUROTOXIC EFFECTS WITH RELEVANCE TO OXIDATIVE STRESS IN AD......Page 426 REFERENCES......Page 427 EFFECTS OF TV3326, TV3279, RASAGILINE, AND TVP 1022 ON sAPPa RELEASE......Page 430 THE EFFECTS OF PKC, MITOGENACTIVATED KINASE (MEK) AND TYROSINE KINASE INHIBITORS ON THE RELEASE OF sAPPα BY PROPARGYLAMINES......Page 431 ACTIVATION OF MAP KINASE BY TV3326 AND TV3279......Page 432 DISCUSSION......Page 433 CONCLUSIONS......Page 436 REFERENCES......Page 437 AMYLOID DEPOSITION AND THE ROLE OF AChE......Page 440 Aβ/AChE COMPLEXES INDUCE NEURODEGENERATION THAT INVOLVES A LOSS OF FUNCTION OF THE WnT SIGNALING......Page 442 REFERENCES......Page 444 EFFECTS OF APOE ON LIPID SYNTHESIS IN THE PRESENCE AND ABSENCE OF EXOGENOUS LIPIDS......Page 446 EFFECTS OF apoE ON THE INCORPORATION OF EXOGENOUS LIPIDS INTO CELLULAR LIPIDS......Page 447 DISCUSSION......Page 449 REFERENCES......Page 450 CORTICAL CHOLINERGIC TERMINATIONS ESTABLISH CLASSICAL SYNAPTIC CONTACTS......Page 452 CORTICAL CHOLINERGIC PRESYNAPTIC BOUTONS BECOME ATROPHIC WITH AGING......Page 453 THE CORTICAL CHOLINERGIC INPUT MAKES PREFERENTIAL SYNAPTIC CONTACTS ON PYRAMIDAL NEURONS—THE IMPACT OF AGING......Page 454 THE NUMBER OF CORTICAL CHOLINERGIC TERMINATIONS IS DEPENDENT ON ENDOGENOUS NGF AND VULNERABLE TO AMYLOID BURDEN......Page 455 REFERENCES......Page 456 RELATIONSHIP BETWEEN NEUROTROPHIN mRNA EXPRESSION AND AChE-POSITIVE AXONAL INGROWTH......Page 458 PATTERNS OF NEURITE OUTGROWTH FROM CHOLINERGIC NEURONS ‘SEEDED’ ONTO ORGANOTYPIC SLICE CULTURES OF HIPPOCAMPUS AND DENTATE GYRUS......Page 460 CONCLUSIONS......Page 462 REFERENCES......Page 463 EXPLORATION OF A NOVEL ENVIRONMENT AND HABITUATION......Page 464 ACQUISITION OF FEAR MEMORY......Page 467 REFERENCES......Page 469 RESTING CHOLINE PLASMA LEVEL......Page 472 HOMEOSTASIS OF SYNAPTIC CHOLINE IN THE BRAIN......Page 473 REFERENCES......Page 474 INTRODUCTION......Page 476 MICRODIALYSIS AND DETERMINATION OF ACh......Page 477 EFFECTS OF GLUCOSE PLUS CHOLINE ON HIPPOCAMPAL ACh RELEASE IN AGED FVB/N MICE......Page 478 EFFECT OF PRECURSOR AVAILABILITY ON ACh SYNTHESIS AND BEHAVIOR......Page 479 IMPLICATIONS OF PRECURSOR EFFECTS FOR THE CONTROL OF ACh SYNTHESIS......Page 480 REFERENCES......Page 481 INTRODUCTION......Page 482 PROPERTIES OF CHOLINERGIC NEURONS......Page 483 CHOLINERGIC NEURONS IN CULTURE......Page 485 REFERENCES......Page 486 CHOLINERGIC THERAPY OF ALZHEIMER’S DISEASE: HOW DID IT START?......Page 488 CLINICAL DATA SUPPORT A STABILIZING EFFECT OF ChEIs......Page 489 PRECLINICAL DATA SUPPORTING A NONSYMPTOMATIC EFFECT OF ChEIs......Page 490 EFFECTS OF ChEIs ON Aβ METABOLISM NOT DEPENDENT ON ChE INHIBITION......Page 491 CONCLUSIONS: HOW CAN THE LONG-TERM EFFECTS OF ChEIs ON AD......Page 492 REFERENCES......Page 493 SUBJECTS AND METHODS......Page 496 RESULTS AND COMMENT......Page 497 REFERENCES......Page 498 IMAGING AND ANALYSIS......Page 500 REFERENCES......Page 505 ACh AND COGNITION IN AD......Page 508 ACh AND BEHAVIORAL CHANGES IN AD......Page 509 REFERENCES......Page 510 INTRODUCTION......Page 512 ACETYLCHOLINE SYNTHESIS......Page 515 NICOTINIC RECEPTORS......Page 516 MUSCARINIC RECEPTORS......Page 518 CHOLINESTERASES......Page 519 ACETYLCHOLINE RELEASE......Page 520 SJOEGREN’S SYNDROME......Page 522 CHOLINERGIC PATHWAYS......Page 523 COGNITION......Page 524 ACKNOWLEDGMENTS......Page 525 REFERENCES......Page 527 64. A single amino acid substitution found in pirimicarb-insensitive acetylcholinesterase of the peach-potato aphid, Myzus persicae (Sulz.)......Page 530 ACTIVITY......Page 532 REFERENCES......Page 533 66. Nicotine induces glutamate release from hippocampal mossy fiber synaptosomes......Page 536 REFERENCES......Page 538 A ROLE FOR MUSCARINIC RECEPTORS IN HUMAN PD......Page 540 A POSSIBLE GENE-ENVIRONMENT INTERACTION MODEL FOR HUMAN PANIC DISORDER: PRIMING THE FIRST ATTACKS THROUGH THE CHOLINERGIC SYSTEM......Page 541 REFERENCES......Page 542 68. A zebrafish mutant as a model for an acetylcholinesterase-deficientvertebrate......Page 544 REFERENCES......Page 546 DRC OF ACh AND EPIBATIDINE AT hα4β2 nACh RECEPTORS......Page 548 ELIMINATION OF PKC PHOSPHORYLATION SITES IN hα4 SUBUNIT INFLUENCES THE NATURE OF EPIBATIDINE DRC......Page 549 REFERENCES......Page 552 RESULTS AND DISCUSSION......Page 554 REFERENCES......Page 556 71. Role of spontaneous mutations of neuronal nicotinic acetylcholine receptors in ADNFLE......Page 558 REFERENCES......Page 560 RECONSTITUTION IN XENOPUS OOCYTES......Page 562 CONCLUSION AND PERSPECTIVES......Page 563 REFERENCES......Page 565 EXPERIMENTAL APPROACH, RESULTS, AND DISCUSSION......Page 566 REFERENCES......Page 568 74. Cholinergic modulation of chemotaxis in human melanoma cells......Page 570 REFERENCES......Page 572 75. Some considerations concerning the molecular mechanism of cholinesterase catalysis......Page 574 REFERENCES......Page 575 ANATOMY......Page 576 POPULATION ACTIVITY IN SMALL NEURONAL NETWORKS......Page 577 INTRINSIC PROPERTIES......Page 579 REFERENCES......Page 580 RESULTS......Page 584 REFERENCES......Page 585 78. Candoxin: a new snake toxin specific for the α7 nicotinic acetylcholine receptor......Page 586 REFERENCES......Page 587 RESULTS AND DISCUSSION......Page 588 REFERENCES......Page 591 MATERIALS AND METHODS......Page 592 RESULTS AND DISCUSSION......Page 593 REFERENCES......Page 594 MODIFICATION OF ΔC-HuAChE BY PEG......Page 596 PHARMACOKINETIC BEHAVIOR OF PEG-HuAChE......Page 597 REFERENCES......Page 598 RESULTS......Page 600 CONCLUSIONS......Page 601 REFERENCES......Page 602 83. A calcium-proton antiport in presynaptic nerve terminals......Page 604 REFERENCES......Page 606 RESULTS......Page 608 REFERENCES......Page 610 85. A peptide from the C-terminal oligomerization domain of human synaptic (T-form) acetylcholinesterase forms classical amyloid fibrils......Page 612 REFERENCES......Page 614 RESULTS......Page 616 CONCLUSIONS......Page 617 REFERENCES......Page 618 COMBINED USE OF DHEA AND DONEPEZIL......Page 620 SUMMARY......Page 621 REFERENCES......Page 622 BINDING EXPERIMENTS......Page 624 DISCUSSION......Page 625 REFERENCES......Page 626 89. NO-dependent and NO-independent cGMP synthesis in cortical cholinergic neurons of the rat brain......Page 628 REFERENCES......Page 630 90. Calcium mobilization and cellular contraction of embryonic lens vesicle and neural tube on muscarinic cholinergic stimulation......Page 632 REFERENCES......Page 634 GAIT......Page 636 SEXUAL DYSFUNCTION......Page 637 REFERENCES......Page 638 INTRODUCTION......Page 640 RESULTS AND DISCUSSION......Page 641 REFERENCES......Page 642 93. Transgenic manipulations of neuromuscular junction maintenance......Page 644 REFERENCES......Page 646 94. Tetanic fade is revealed by blocking presynaptic nicotinic receptors containing α3β2 subunits after reducing the safety factor of neuromuscular transmission......Page 648 REFERENCES......Page 650 ISOLATION AND CLONING OF α10......Page 652 ELECTROPHYSIOLOGICAL RECORDINGS......Page 653 RESULTS......Page 654 REFERENCES......Page 656 AChE ASSAYS......Page 658 DISCUSSION......Page 659 REFERENCES......Page 660 REACTION WITH SUBSTRATES......Page 662 KINETICS OF THE REACTION......Page 663 REFERENCES......Page 664 WATER PROPERTIES......Page 666 REFERENCES......Page 667 99. α-Conotoxins PnIA and [A10L]PnIA stabilize different states of the chick neuronal α7 acetylcholine receptor......Page 668 REFERENCES......Page 669 100. Acetylcholinesterase knockout mice have increased sensitivity to scopolamine and atropine......Page 670 REFERENCES......Page 671 101. Investigating the diversity of acetylcholinesterase in insect species......Page 672 REFERENCE......Page 673 RESULTS......Page 674 REFERENCES......Page 675 IMMUNOLOCALIZATION STUDIES......Page 676 REFERENCES......Page 677 RESULTS AND DISCUSSION......Page 678 REFERENCES......Page 681 105. Mapping the acetylcholine-binding sites of Torpedo nicotinic receptor using photoaffinity labeling: past, present, and future......Page 684 REFERENCES......Page 686 RESULTS AND DISCUSSION......Page 688 REFERENCES......Page 689 RESULTS AND DISCUSSION......Page 690 REFERENCES......Page 693 108. Identification and characterization of a diverse family of neurotoxin-like peptides from the South American coral snake......Page 694 AChE−/− MICE ARE RESISTANT TO OXOTREMORINE (OXO)-INDUCED HYPOTHERMIA, TREMOR, SALIVATION, AND ANALGESIA......Page 696 MUSCARINIC RECEPTOR mRNA LEVELS ARE UNCHANGED IN AChE−/− MICE......Page 697 REFERENCES......Page 698 ENZYME EXTRACTION......Page 700 RESULTS......Page 701 DISCUSSION......Page 702 REFERENCES......Page 703 INTRODUCTION......Page 704 EFFECTS OF MUTATIONS ON HI-6-INDUCED REACTIVATION OF OP-INHIBITED MOUSE AChE......Page 705 DISCUSSION......Page 706 REFERENCES......Page 707 GALANTHAMINE INTERACTS WITH THE CATALYTIC AND THE PERIPHERAL ANIONIC SITE OF AChE......Page 708 REFERENCES......Page 709 DIFFERENTIATION OF NEURONS AND NMJs......Page 712 REFERENCES......Page 713 INTRODUCTION......Page 714 RESULTS......Page 715 REFERENCES......Page 717 INTRODUCTION......Page 718 REFERENCES......Page 719 GENERAL CONCLUSIONS......Page 722 REFERENCES......Page 725 RADIAL ARM MAZE......Page 726 REFERENCES......Page 727 IN VITRO METHODS......Page 728 REFERENCES......Page 729 RESULTS......Page 730 REFERENCES......Page 731 120. Fine-tuning modulation of neuronal muscarinic M1 (facilitatory) and M2 (inhibitory) receptor activation by adenosine at the rat neuromuscular junction......Page 732 REFERENCES......Page 733 RESULTS AND DISCUSSION......Page 736 REFERENCES......Page 738 REFERENCES......Page 740 123. Segregation of phosphatidic acid-rich domains in reconstituted acetylcholine receptor membranes......Page 742 ACKNOWLEDGMENT......Page 743 REFERENCES......Page 744 RESULTS......Page 746 REFERENCES......Page 747 RESULTS AND DISCUSSION......Page 750 REFERENCES......Page 751 THE DETECTION OF UNWANTED ChE-BOUND HIDDEN LIGANDS......Page 752 REFERENCES......Page 754 127. Plant cholinesterase activity as a biosensor; cellular models......Page 756 REFERENCES......Page 757 128. Studies on the mechanism of blockade of acetylcholine release by snake presynaptic PLA2 neurotoxins......Page 758 REFERENCES......Page 760 129. Variability of substrate specificity in cholinesterases of vertebrates and invertebrates......Page 762 REFERENCES......Page 763 GLIOTACTIN—THE EXTRACELLULAR DOMAIN......Page 764 GLIOTACTIN—THE CYTOPLASMIC DOMAIN......Page 765 REFERENCES......Page 766 131. Targeting of the vesicular acetylcholine transporter to cholinergic subdivisions in transgenic mice......Page 768 REFERENCES......Page 770 132. Ligand-induced conformational changes in the omega loop of acetylcholinesterase revealed by fluorescence spectroscopy......Page 772 REFERENCES......Page 773 133. ‘Readthrough’ acetylcholinesterase and cholinergic neurotransmission......Page 774 ACKNOWLEDGMENTS......Page 776 REFERENCES......Page 777 RESULTS AND DISCUSSION......Page 778 REFERENCES......Page 780 RESULTS AND DISCUSSION......Page 782 REFERENCES......Page 783 136. Two-hybrid approach to the intracellular function(s) of readthrough acetylcholinesterase......Page 784 REFERENCES......Page 786 AChE DETERMINATION......Page 788 DISCUSSION......Page 789 REFERENCES......Page 790 138. Effects of carbamate insecticides on rat neuronal α4β4 nicotinic receptors and rat brain acetylcholinesterase......Page 792 REFERENCES......Page 793 CHOLINE SENSITIVITY OF CURRENTS AND CALCIUM INFLUX......Page 794 CONCLUSIONS......Page 795 REFERENCES......Page 796 THEORY......Page 798 RESULTS AND DISCUSSION......Page 801 REFERENCES......Page 803 ALTERNATIVE PASSAGES TO THE ACTIVE SITE......Page 804 REFERENCES......Page 805 STRESS......Page 806 REFERENCES......Page 807 143. Probing the binding interface between the nicotinic acetylcholine receptor and a short α-neurotoxin through receptor-biotinyltoxin-streptavidin ternary complexes......Page 808 HupA AND Tac PROTECT NG108-15 CELLS FROM STAU-INDUCED APOPTOSIS......Page 810 THE ANTI-APOPTOTIC EFFECTS OF HupA AND Tac ARE RELATED TO AChE INHIBITION IN APOPTOTIC CELLS......Page 811 MODULATIONS OF Bax AND Bcl-2 PROTEIN EXPRESSION ARE INVOLVED IN THE ANTI-APOPTOTIC EFFECTS OF HupA AND Tac......Page 813 REFERENCES......Page 814 RESULTS......Page 816 REFERENCES......Page 817 STATISTICAL ANALYSIS......Page 818 DISCUSSION......Page 819 REFERENCES......Page 820 RESULTS......Page 822 REFERENCES......Page 823 148. Use of the morphing graphics technique to visualize conformational differences between acetylcholinesterases from different species and inhibitor-induced conformational changes......Page 824 REFERENCES......Page 825 MATERIALS AND METHODS......Page 828 RESULTS......Page 829 DISCUSSION......Page 830 REFERENCES......Page 831 RESULTS AND DISCUSSION......Page 834 ACKNOWLEDGMENT......Page 836 REFERENCES......Page 837 Index......Page 838