Enzymes of the Cholinesterase Family
Edited by
Daniel M. Quinn University of Iowa Iowa City, Iowa
A. S. Balasubramanian Christian Medical College and Hospital Vellore, Tamil Nadu, India
Bhupendra P. Doctor Walter Reed Army Institute of Research Washington, D.C.
and
Palmer Taylor University of California at San Diego La Jolla, California
Springer Science+Business Media, LLC
Library of Congress Cataloglng-ln-PublIcatIon Data
Enzymes of the C h o l i n e s t e r a s e family / ed i t e d by Daniel M. Quinn ... [e t a l . ] .
p. cm. "Proceedings of the F i f t h I n t e r n a t i o n a l Meeting on
C h o i i n e s t e r a s e s , held September 24-28, 1994, in Madras, I n d i a " — T . p . verso.
Includes b i b l i o g r a p h i c a l r e f e r e n c e s and index. ISBN 978-1-4899-1053-0 1. C h o i i n e s t e r a s e s — C o n g r e s s e s . I. Quinn, Daniel M.
I I . I n t e r n a t i o n a l Meeting on C h o i i n e s t e r a s e s (5th : 1994 : Madras, Indi a ) [DNLM: 1. A c e t y l c h o l i n e s t e r a s e — m e t a b o l i s m — c o n g r e s s e s .
2. B u t y r y l c h o l I n e s t e r a s e — m e t a b o l i s m — c o n g r e s s e s . QU 136E611 1995] QP609.C4E56 1995 574. 19'253~dc20 DNLM/DLC for Library of Congress 95-39179
CIP
Front cover: A model of the complex between the snake venom toxin fasciculin (light color) and acetylcholinesterase (dark color), constructed by H.K.L. van den Born et ai [(1995) Protein Science 4, 703—715]. Photography by Z. Radie of the University of California at San Diego.
Proceedings of the Fifth International Meeting on Cholinesterases, held September 24-28, 1994, in Madras, India
ISBN 978-1-4899-1053-0 ISBN 978-1-4899-1051-6 (eBook) DOI 10.1007/978-1-4899-1051-6
© Springer Science+Business Media New York 1995 Originally published by Plenum Press, New York in 1995 Softcover reprint of the hardcover 1st edition 1995
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PREFACE
The Fifth International Meeting on Cholinesterases convened in Madras, India, in September of 1994. The long and rich history and culture of India provided an excellent setting for the meeting. More than 120 delegates from Asia, Australia, Europe and North America heard 54 oral presentations and viewed 54 posters on current research on enzymes of the cholinesterase family. The aim of this book is to compile the presentations of the Fifth International Meeting on Cholinesterases into a volume that describes recent investigations on the structure and catalytic function of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and related enzymes, as well as studies on the molecular and cellular biology of these enzymes and the genes which encode them.
Cholinesterases enjoy a long and storied history in diverse areas. In basic biochemical research, AChE is one of the best studied, though yet enigmatic, of enzymes. The efficient catalytic function of this enzyme presents the biochemist with a fundamental challenge in understanding the relationship between structure and function. AChE and BuChE belong to a family of proteins, the alB hydrolase fold family, whose constituents evolutionarily diverged from a common ancestor. Proteins in this family have a wide range of physiological functions. In commerce, AChE is a prime target for agricultural insect control, and for the development of therapeutic agents for Alzheimer's disease. On the national security front, AChE is the target of chemical warfare agents, "nerve gases," which pose a threat on the battlefield of nations at war and in the city centers of nations at peace. Recent events, chronicled in the international news media, provide a stark reminder of this fact.
The broad reach of cholinesterase function and research affects the biological scientist and nonscientist alike. From biotechnology to the military, one is hard pressed to find a family of enzymes whose effect on the human condition is more pervasive. Various presentations at the meeting described structure-activity relationships for the interaction of cholinesterases with toxic organophosphorus agents. Novel efforts at antidotal therapy were described that aim to use cholinesterases in the presence of nucleophilic oximes to detoxify organophosphorus inhibitors. Strategies for effective inhibition of acetylcholinesterase in the central nervous system, as an approach to the treatment of the cognitive dis functions associated with Alzheimer's disease, were described, as were the structure-activity relationships of new anti-Alzheimer's agents.
The cell and molecular biology of cholinesterases is advancing rapidly. The relationships between AChE gene structure and the various molecular forms of the enzyme were described at the meeting, as were the mechanisms of gene expression, cellular biosynthesis, and assembly of the cholinesterases. Various noncatalytic roles for cholinesterases were described, which include involvement in nervous system development and in neurotransmission involving dopamine-containing nerve terminals.
v
vi Preface
Reports of structure-function relationships not only described the fine detail that is emerging on the structural basis of the rapid catalytic mechanisms effected by cholinesterases, but also provided the bases for several controversies. X-ray crystallography of catalytically relevant ligand complexes with AChE provided visual verification of the roles, suggested by site-directed mutagenesis and other studies, for loci in the active site that are responsible for acyl group specificity, quaternary ammonium recognition, oxyanion recognition and acid-base catalysis. The crystal structure of AChE provided the template for theoretical evaluation ofthe role of the electrical field of the enzyme in ligand binding. Good spirited controversies arose on whether the electrical field of the enzyme plays a significant role in the rapidity of AChE catalysis, and whether an anthropomorphic "back door" mechanism is required for release of cationic products.
This Preface outlines just a fraction of the wide range of topics discussed at the Fifth International Meeting on Cholinesterases in Madras, India. The chapters that follow provide a clear view of the breadth and vigor of research on enzymes of the cholinesterase family. The meeting in Madras was a once in a lifetime opportunity for an international delegation to discuss and debate such research in a congenial atmosphere. Our Indian hosts are to be commended for the graciousness and organizational effort that were key to the success of the meeting.
Daniel M. Quinn A. s. Balasubramanian Bhupendra P. Doctor Palmer Taylor
CONTENTS
Part I. GENE STRUCTURE AND EXPRESSION OF CHOLINESTERASES
A. Presentations
Antisense Oligonucleotides Suppressing Expression of Cholinesterase Genes Modulate Hematopoiesis in Vivo and ex Vivo ....................... .
Hermona Soreq, Efrat Lev-Lehman, Deborah Patinkin, Mirta Grifman, Gal Ehrlich, Dalia Ginzberg, Fritz Eckstein, and Haim Zakut
Properties of Class A Acetylcholinesterase, the Enzyme Encoded by ACE-I in Caenorhabditis elegans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Martine Arpagaus, Nathalie Schirru, Emmanuel Culetto, Vincenzo Talesa, Xavier Cousin, Arnaud Chatonnet, Yann Fedon, Jean-Baptiste Berge, Didier Fournier, and Jean-Pierre Toutant
Ligand Specificity and Gene Expression in the Cholinergic Synapse: A Comparison between Acetylcholinesterase and the Nicotinic Acetylcholine Receptor.. 15
Palmer Taylor, Zoran Radic, Hans-JUrgen Kreienkamp, Zhigang Luo, Natilie A. Pickering, and Shelley Camp
Butyrylcholinesterase Transcription Start Site and Promoter ..................... 23 Omar Jbilo, Jean-Pierre Toutant, Arnaud Chatonnet, and Oksana Lockridge
The C-Terminal Alternative Regions of Acetylcholinesterase. . . . . . . . . . . . . . . . . . . .. 29 Jean Massoulie, Alain Anselmet, Suzanne Bon, Fran<,:oise Coussen,
Eric Krejci, and Claire Legay
Developmental Expression of Acetylcholinesterase in Skeletal Muscle. . . . . . . . . . . .. 37 Zoran Grubic and Armand F. Miranda
vii
viii Contents
B. Posters
Alternative Exon 6 Directs Synaptic Localization of Recombinant Human Acetylcholinesterase in Neuromuscular Junctions of Xenopus laevis Embryos ..................................................... 45
Meira Sternfeld, Shlomo Seidman, Revital Ben Aziz-Aloya, Michael Shapira, Rina Timberg, Daniela Kaufer, and Hermona Soreq
Developmental Regulation of Acetylcholinesterase mRNA in the Mouse Diaphragm: Alternative Splicing and Focalization ............................. 47
Claire Legay, Monique Huchet, Jean Massoulit\ and Jean-Pierre Changeux
Acetylcholinesterase and Butyrylcholinesterase Expression in Adult Rabbit Tissues and during Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
Omar Jbilo, Yann L'Hermite, Vincenzo Talesa, Jean-Pierre Toutant, and Arnaud Chatonnet
Mutations in the Catalytic Subunit of Acetylcholinesterase Do Not Appear Responsible for Congenital Myasthenic Syndrome Associated with End-Plate Acetylcholinesterase Deficiency ......................... 51
S. Camp, A. G. Engel, D. K. Getman, S. Bon, J. Massoulie, and P. Taylor
Regulation of Acetylcholinesterase (AChE) mRNA by Ryanodine-Sensitive and L-Type Calcium Channels during Myogenesis in Vitro and Muscle Development in Vivo . .......................................... 53
Zhigang Luo, Martine Pincon-Raymond, and Palmer Taylor
Regulation of AChE Gene Expression in Neuronally Induced Mouse P19 Cells. . . . .. 55 B. A. Coleman and P. Taylor
Regulation of Human Acetylcholinesterase Gene Expression. . . . . . . . . . . . . . . . . . . .. 56 D. Getman, K. Inoue, and P. Taylor
Promoter Elements of the Mouse Acetylcholinesterase Gene: Regulation during Muscle Differentiation ......................................... 57
Annick Mutero and Palmer Taylor
Part II. POLYMORPHISM AND STRUCTURE OF CHOLINESTERASES
A. Presentations
Structures of Complexes of Acetylcholinesterase with Covalently and Non-Covalently Bound Inhibitors ................................ 59
J. L. Sussman, M. Harel, M. Raves, D. M. Quinn, H. K. Nair, and I. Silman
Electrostatic Properties of Human Acetylcholinesterase. . . . . . . . . . . . . . . . . . . . . . . .. 67 Daniel R. Ripoll, Carlos H. Faerman, Richard Gillilan, Israel Silman, and
Joel L. Sussman
Contents ix
Substrate Binding Site and the Role of the FLAP Loop in Candida rugosa Lipase, a Close Relative of Acetylcholinesterase. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71
Miroslaw Cygler, Pawel Grochulski, and Joseph D. Schrag
Studies on Partially Unfolded States of Torpedo californica Acetylcholinesterase 77 Israel Silman, David I. Kreimer, Irina Shin, Elena A. Dolginova, Ester Roth,
Daniella Goldfarb, Reuven Szosenfogel, Mia Raves, Joel L. Sussman, Nina Borochov, and Lev Weiner
FTIR-Spectroscopic Investigations of the Structure and Temperature Stability of the Acetylcholinesterase from Torpedo californica .. . . . . . . . . . . . . . . . . . . .. 83
Ferdinand Hucho, Dieter Naumann, and Ute Gome-Tschelnokow
Residues in the C-Terminus of Torpedo californica Acetylcholinesterase Important for Modification into a Glycophospholipid Anchored Form . . . . . . . . . . .. 89
Goran Bucht, Lena Lindgren, and Karin Hjalmarsson
Computer Modeling of Acetylcholinesterase and Acetylcholinesterase-Ligand Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 97
S. T. Wlodek, J. Antosiewicz, M. K. Gilson, 1. A. McCammon, T. W. Clark, and L.R. Scott
Structural Analysis of the Asparagine-Linked Oligosaccharides ofCholinesterases: N-Linked Carbohydrates of Cholinesterases ........................ 105
Ashima Saxena and B. P. Doctor
Pressure Effects on Structure and Activity of Cholinesterase ..................... 113 P. Masson and C. Clery
B. Posters
Hydrophobicity on Esterase Activity of Human Serum Cholinesterase ............. 123 L. Jaganathan, K. Padmalatha, G. Revathi, and R. Boopathy
Alterations in the Topography of Acetylcholinesterase Active Site Gorge after Binding of Peripheral Anionic Site Ligands ......................... 125
Anton Stalc, Zoran Grubic, Marjeta Sentjurc, Slavko Pecar , Mary K. Gentry, and Bhupendra P. Doctor
Acetylcholinesterase from Octopus vulgaris (Cephalopoda): Evidence for a Specific High Salt-Soluble and Heparin-Soluble Fraction of Globular Forms ..... 127
Vincenzo Talesa, Marta Grauso, Elvio Giovannini, Gabriella Rosi, and Jean-Pierre Toutant
Molecular Polymorphism of Acetylcholinesterase in Hirudo medicinalis ........... 128 Vincenzo Talesa, Marta Grauso, Elvio Giovannini, Gabriella Rosi, and
Jean-Pierre Toutant
Subunit Association and Stabilization of Butyrylcholinesterase (BChE) ............ 129 R. M. Blong, P. Masson, and O. Lockridge
x Contents
Denaturation of Recombinant Human Acetylcholinesterase ...................... 131 M. Lebleu, C. Clery, P. Masson, S. Reuveny, D. Marcus, B. Velan, and
A. Shafferman
Part III. MECHANISM OF CATALYSIS OF CHOLINESTERASES
A. Presentations
Amino Acid Residues that Control Mono- and Bisquatemary Oxime-Induced Reactivation of O-Ethyl Methylphosphonylated Cholinesterases ........ 133
Y. Ashani, Z. Radic, I. Tsigelny, D. C. Vellom, N. A Pickering, D. M. Quinn, B. P. Doctor, and P. Taylor
Modulation of Catalysis and Inhibition of Fetal Bovine Serum Acetylcholinesterase by Monoclonal Antibodies ...................................... 141
B. P. Doctor, Mary K. Gentry, Ashima Saxena, and Yacov Ashani
Insect Acetylcholinesterase and Resistance to Insecticides ....................... 149 Didier Fournier, Marie Maturano, Laurent Gagnoux, Philippe Ziliani,
Cyril Pertuy, Madeleine Pralavorio, Jean-Marc Bride, Leila Elmarbouh, Alain Klaebe, and Patrick Masson
Phosphonate Ester Active Site Probes of Acetylcholinesterase, Trypsin and Chymotrypsin ................................................ 155
Akos Bencsura, Istvan Enyedy, Carol Viragh, Rinat Akhmetshin, and Ildiko M. Kovach
Irreversible Site-Directed Labeling Studies on Cholinesterases ................... 163 L. Ehret-Sabatier, I. Schalk, C. Loeb, F. Nachon, and M. Goeldner
Mutation of Human Butyrylcholinesterase Glycine 117 to Histidine Preserves Activity but Confers Resistance to Organophosphorus Inhibitors ....... 169
C. A Broomfield, C. B. Millard, o. Lockridge, and T. L. Caviston
Reaction of Acetylcholinesterase with Organophosphonates: Molecular Fate at the Rim of a Gorge ............................................... 177
Harvey Alan Berman
Amino Acid Residues in Acetylcholinesterase which Influence Fasciculin Inhibition .. 183 Zoran Radic, Daniel M. Quinn, Daniel C. Vellom, Shelley Camp, and
Palmer Taylor
Molecular Aspects of Catalysis and of Allosteric Regulation of Aceytlcholinesterases 189 A. Shaff erman, AOrdentlich, D. Barak, C. Kronman, N. Ariel, M. Leitner,
Y. Segall, A. Bromberg, S. Reuveny, D. Marcus, T. Bino, A. Lazar, S. Cohen, and B.Velan
Contents xi
Structural Determinants ofFasciculin Specificity for Acetylcholinesterase .......... 197 Pascale Marchot, Shelley Camp, Zoran Radic, Pierre E. Bougis, and
Palmer Taylor
The Function of Electrostatics in Acetylcholinesterase Catalysis .................. 203 Daniel M. Quinn, Javier Seravalli, Haridasan K. Nair, Rohit Medhekar,
Basel Husseini, Zoran Radic, Daniel C. Vellom, Natilie Pickering, and Palmer Taylor
Fasciculin 2 Binds to the Peripheral Site on Acetylcholinesterase and Inhibits Substrate Hydrolysis by Slowing a Step Involving Proton Transfer during Enzyme Acylation ....................................... 209
Jean Eastman, Erica J. Wilson, Carlos Cervenansky, and Terrone L. Rosenberry
B. Posters
New Photolabile Inhibitors ofCholinesterases Designed for Rapid Photochemical Release of Choline ............................................. 219
L. Peng and M. Goeldner
Amino Acids Determining Specificity to OP-Agents and Facilitating the "Aging" Process in Human Acetylcholinesterase ............................ 221
A. Ordentlich, C. Kronman, D. Stein, N. Ariel, S. Reuveny, D. Marcus, y. Segall, D.Barak, B. Velan, and A.Shafferman
Electrostatic Attraction by Surface Charge does not Contribute to the Catalytic Efficiency of Acetylcholinesterase ................................ 223
D. Barak, A. Ordentlich, C. Kronman, R. Ber, T. Bino, N.Ariel, R. Osman, B. Velan, and A. Shafferman
Catalytic Properties of Human Serum Cholinesterase Phenotypes in their Reaction with Substrates and Inhibitors .................................... 225
V. Simeon-Rudolf, M. Skrinjaric-Spoljar, and E. Reiner
Organophosphate Specificity of Acyl Pocket Cholinesterase Mutants ............... 227 Natilie A. Pickering, Palmer Taylor, and Harvey Berman
London Dispersion Interactions in Molecular Recognition by Acetylcholinesterase ... 228 Daniel M. Quinn, Haridasan K. Nair, Javier Seravalli, Keun Lee,
Tomira Arbuckle, Zoran Radic, Daniel C. Vellom, Natilie Pickering, and Palmer Taylor
Peripheral Anionic Site of Wild-Type and Mutant Human Butyrylcholinesterase ..... 230 P. Masson, M.T. Froment, C. Bartels, and o. Lockridge
xii Contents
Part IV. CELLULAR BIOLOGY OF CHOLINESTERASES
A. Presentations
Dual Control of Acetylcholinesterase Content of Mature Innervated Fast Muscles .... 233 Victor Gisiger
Restricted Regulation of AChE Transcription, Translation, and Localization: Individual Nuclei Respond to Locally Generated Signals in Multinucleated Skeletal Muscle Fibers ............................. 239
Richard L. Rotundo, Susana G. Rossi, Rosely O. Godinho, Ana E. Vazquez, and Bhavya Trivedi
Mechanism and Implications of Selective Neural Lesions by Acetylcholinesterase Antibodies in the Central and Peripheral Nervous Systems: AChE Autoimmunity ................................................ 247
S. Brimijoin, P. Hammond,and Z. Rakonczay
Neural Regulation of Acetylcholinesterase Expression in Slow and Fast Muscles of the Rat ...................................................... 253
J. Sketelj and B. Cresnar
Neuromuscular Factors Influencing Acetylcholinesterase Gene Expression in Skeletal Muscle Fibers ......................................... 261
B. J. Jasmin, C. Boudreau-Lariviere, R. Chan, D. A. Hubatsch, and H. Sveistrup
Post-Translation Processing of Acetylcholinesterase: Cellular Control of Biogenesis and Secretion ................................................. 269
Baruch Velan, Chanoch Kronman, Arie Ordentlich, Yehuda Flashner, Raphael Ber, Sara Cohen, and Avigdor Shafferman
Acetylcholinesterase at Neuromuscular Junctions: Density, Catalytic Turnover, and Molecular Forms with Modeling and Physiological Implications ........ 277
L. Anglister, J. R. Stiles, B. Haesaert, J. Eichler, and M. M. Salpeter
B. Posters
Effect of Acute Irreversible Inhibition of Acetylcholinesterase on Nerve Stimulation-Evoked Contractile Properties of Rat Medial Gastrocnemius 287
R. Panenic, P. Gardiner, and V. Gisiger
Developmental Regulations of Acetylcholinesterase at the Molecular Level in the Central Nervous System of the Quail .............................. 288
Alain Anselmet, Jean-Marc Chatel, and Jean Massoulie
Contents xiii
Reversal of Glycerol Ether-Stimulated Acetylcholinesterase Activity by c-fos Antisense Oligonucleotide in Primary Neuronal Cultures .............. 289
J. R. Dave, E. Fasnacht, F. C. Tortella, J. M. Best, B. P. Doctor, and H. S. Ved
Acetylcholinesterase Activity in Plants ...................................... 291 S. Madhavan, Gautam Sarath, and Patricia L. Herman
Signal-Mediated Cellular Retention and Subunit Assembly of Human Acetylcholinesterase ........................................... 293
C. Kronman, Y. Flashner, A. Shaff erman, and B. Velan
The Grain Aphid Cholinesterases ........................................... 295 B. Leszczynski, T. Bakowski, A.F.G. Dixon, and H. Matok
Part V. STRUCTURE-FUNCTION RELATIONSHIPS OF ANTICHOLINESTERASE AGENTS
A. Presentations
Review of Nerve Agent Inhibitors and Reactivators of Acetylcholinesterase ......... 297 David H. Moore, Charles B. Clifford, Isabelle T. Crawford, Greg M. Cole,
and Jack M. Baggett
Organophosphate-Sensitive Cholinergic Receptors: Possible Role in Modulation of Anticholinesterase-Induced Toxicity .............................. 305
C. N. Pope, J. Chaudhuri, and T. K. Chakraborti
Effect of Physic all Chemical Stressors on the Cholinergic System in Rat ............ 313 Satu M. Somani
Evaluation of the Direct Actions ofHI-6 in Reversing Soman-Induced Tetanic Fade .. 321 Michael Adler, Donald M. Maxwell, Richard E. Sweeney, and
Sharad S. Deshpande
Clinical Blood Cholinesterase Measurements for Monitoring Pesticide Exposures .... 329 B. W. Wilson, S. Padilla, J. R. Sanborn, J. D. Henderson, and J. E. Billitti
Repeated Dosing with Chlorpyrifos Increases Acetylcholinesterase Immunoreactivity in Rat Brain ................................... 337
S. Padilla, S. Chiappa, C. Koenigsberger, V. Moser, and S. Brimijoin
Bisquaternary Oximes as Antidotes against Tabun and Soman Poisoning: Antidotal Efficacy in Relation to Cholinesterase Reactivation .................. 345
G. Amitai, I. Rabinovitz, G. Zomber, R. Chen, G. Cohen, R. Adani, and L. Raveh
xiv Contents
Comparison of Acetylcholinesterase, Pyrldostigmine, and HI-6 as Antidotes against Organophosphorus Compounds .................................. 353
Donald M. Maxwell, Karen M. Brecht, Ashima Saxena, Palmer Taylor, and Bhupendra P. Doctor
Inhalation Toxicokinetics ofC(±)P(±)-Soman and (±)-Sarin in the Guinea Pig ....... 361 H. P. Benschop, L. P. A. de Jong, and 1. P.Langenberg
Inhibition ofFish Brain Acetylcholinesterase by Cadmium and Mercury: Interaction with Selenium ................................................ 369
S. Sen, S. Mondal, 1. Adhikari, D. Sarkar, S. Bose, B. Mukhopadhyay, and Shelley Bhattacharya
Pharmacological Evaluation of Antidotes against Organophosphorus Intoxication .... 375 S. N. Dube, R. Bhattacharya, K. Husain and A. K. Sikder
Medical Protection against Organophosphorus Toxicity ......................... 381 S. Das Gupta
B. Posters
Identification of a 155 kDa Fraction That Possesses Neuropathy Target Esterase Activity ..................................................... 387
C. E. Mackay, B. D. Hammock, and B. W. Wilson
Interleukin 6 Modulates AChE Activity in CNS Neurons ........................ 389 D. Claren90n, E. Multon, M. Galonnier, M. Estrade, C. Fournier,
J. Mathieu, J. C. Mestries, G. Testylier, P. Gourmelon, and A. Fatome
HI-6 is Incapable of Reactivating Tabun-Phosphonylated Human Acetylcholinesterase ........................................... 391
Chunyuan Luo, Jinsheng Yang, and Manji Sun
Pattern ofInhibition of Acetylcholinesterases in Different Regions of the Brain by Two Organophosphorus Homologues, in Relation to Their Differential Neurotoxicity ................................................. 392
P. Santhoshkumar, Subramanya Karanth, and T. Shivanandappa
Organophosphate-Sensitive Carboxyl esterase Isozyme(S) in the Rat Liver .......... 394 Subramanya Karanth and T. Shivanandappa
Fenthion Treatment Produces Tissue-, Dose-, and Time-Dependent Decreases in Muscarinic Second Messenger Response in the Adult Rat CNS ......... 396
P. Tandon, C. N. Pope, S. Barone, Jr., W. Boyes, H. A. Tilson, and S. Padilla
Protection of Guinea Pigs against Soman Inhalation by Pretreatment Alone with Human Butyrylcholinesterase .................................... 398
N. Allon, L. Raveh, E. Gilat, J. Grunwald, E. Manistersky, E. Cohen, and Y. Ashani
Contents xv
Human Butyrylcholinesterase as Prophylaxis Treatment against Soman: Behavioral Test in Rhesus Monkeys ........................................ 400
E. Grauer, L. Raveh, J. Kapon, J. Grunwald, E. Cohen, and Y. Ashani
Efficacy of Prophylaxis with Human Butyrylcholinesterase against Soman and VX Poisoning: A Comparative Analysis ............................... 402
L. Raveh, J. Grunwald, E. Cohen, and Y. Ashani
Prevention of Brain Damage and Behavioral Performance Changes following an IV· Injection of Soman and VX in Rats Pretreated with Human Butyrylcholinesterase .......................................... 404
T. Kadar, L. Raveh, R. Brandeis, J. Grunwald, E. Cohen, and Y. Ashani
Inactivation of the Catalytic Activities in Human Serum Butyrylcholinesterase by Metal Chelators ............................................... 406
C. D. Bhanumathy and A. S. Balasubramanian
Protective Efficacy of Physostigmine and Pyridostigmine at Various Pretreatment Times against Inhaled Sarin in Rats ............................... 408
R. Vijayaraghavan, K. Husain, P. Kumar, K. S. Pandey, and S. Das Gupta
Induction of Carboxylesterase Isoenzymes and Altered Acetylcholinesterase during OP Resistance in Mosquito Culex quinquefasciatus .................. 410
N. Gopalan, S. Prakash, K. M. Rao, and B. K. Bhattacharya
Structure-Activity ofPyridinium Oximes as Antidotes to Organophosphorus Anticholinesterase Agents ....................................... 412
A. K. Sikder, S. N. Dube, and D. K. Jaiswal
Part VI. NONCHOLINERGIC FUNCTIONS OF CHOLINESTERASES
A. Presentations
A Non-Cholinergic Function for Acetylcholinesterase .......................... 415 S. A. Greenfield
Non-Cholinergic Function of Cholinesterases ................................. 423 K. M. Kutty, V. Prabhakaran, and A. R. Cooper
Glycosylated Inactive Forms of Chicken Butyrylcholinesterases and Their Possible Functions .................................................... 427
Paul G. Layer, Christoph Ebert, Sven Treskatis, Thomas Weikert, and Elmar Willbold
Possible Cholinergic and Non-Cholinergic Actions of Transiently Expressed Acetylcholinesterase in Thalamocortical Development Projections ...... 435
Richard T. Robertson, Ron S. Broide, Jen Yu, and Frances L. Leslie
xvi Contents
B. Posters
Evidence for a Putative Acetylcholinesterase Uptake Mechanism within the Substantia Nigra .............................................. 443
T. C. Budd, B. G. M. Dickie, D. Vaux, and S. A. Greenfield
Activation of Peritoneal Macrophages by Acetylcholinesterase Is Independent of Catalytic Activity .............................................. 445
A. Klegeris, T. C. Budd, and S. A. Greenfield
Functional Significance ofButyrylcholinesterase for Formation of Neural Networks as Tested by Chicken Retinospheroids ............................. 447
Elmar Willbold and Paul G. Layer
Neurotrophic Function of Circulating Acetylcholinesterase in Ap/ysia ............. 449 M. Srivatsan and B. Peretz
Part VII. PHARMACOLOGICAL UTILIZATION OF ANTICHOLINESTERASES
A. Presentations
Cholinesterases in Alzheimer's Disease ...................................... 451 M.-Marsel Mesulam
A Role for Acetylcholine and Acetylcholinesterase in the Regulation of Neurite Outgrowth: Implications for Alzheimer's Disease .................... 455
D. H. Small and G. Reed
Cholinesterase Inhibitors: From Preclinical Studies to Clinical Efficacy in Alzheimer Disease ...................................................... 463
E. Giacobini
B. Posters
Genetic Predisposition for Variable Response to Anticholinesterase Therapy Anticipated in Carriers of the Butyrylcholinesterase "Atypical" Mutation 471
Y. Loewenstein, M. Schwarz, D. Glick, B. Norgaard-Pedersen, H. Zakut, andH. Soreq
Horse Serum Butyrylcholinesterase Does Not Disrupt Passive Avoidance Learning or Spontaneous Motor Activity in Rats ............................ 473
Raymond F. Genovese, Averi R. Roberts, William E. Fantegrossi, Roberta Larrison, and Bhupendra P. Doctor
Acetylcholinesterase Inhibitors (AChE-I) as a Potential Use for Alzheimer's Disease (AD) Therapy: Differences in Mechanisms of Enzyme Inhibition ....... 475
Albert Enz
Contents xvii
Comparative Inhibition of Acetylcholinesterase by Tacrine, Physostigmine, and Huperzine in the Adult Rat Brain ................................. 477
H. S. Ved, 1. M. Best, J. R. Dave, and B. P. Doctor
Acetylcholinesterase Gene Sequence and Copy Number are Normal in Alzheimer's Disease Patients Treated with the Organophosphate Metrifonate ........ 479
C. F. Bartels, P. L. Moriearty, R. E. Becker, C. P. Mountjoy, and O. Lockridge
Part VIII. APPENDICES
Appendix I
Compilation of Evaluated Mutants of Cholinesterases .......................... 481 A. Shaff erman, C. Kronman, and A. Ordentlich
Appendix II
A Database of Sequences Related to AcetylcholinesteraselLipase/a:p Hydrolase Superfamily with Public Access on Internet ........... ' .............. 489
Xavier Cousin, Thierry Hotelier, Catherine Mazzoni, Martine Arpagaus, Jean-Pierre Toutant, and Arnaud Chatonnet
Appendix III
Amino Acid Alignment of Cholinesterases, Esterases, Lipases, and Related Proteins .. 493 Mary K. Gentry and B. P. Doctor
Appendix IV
Participants ............................................................ 507
Author Index ........................................................... 517
Subject Index ........................................................... 521