Abramson SN

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Full name : Abramson Stewart N

First name : Stewart N

Mail : Department of Pharmacology M -036, University of California, San Diego,La Jolla, CA 92093

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Country : USA

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Phone : (I) 6195345626

Fax : (I) 619 534 6833

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References (8)

Title : Lophotoxin-insensitive nematode nicotinic acetylcholine receptors - Tornoe_1996_J.Exp.Biol_199_2161
Author(s) : Tornoe C , Holden-Dye L , Garland C , Abramson SN , Fleming JT , Sattelle DB
Ref : J Exp Biol , 199 :2161 , 1996
Abstract : Nematode nicotinic acetylcholine receptors (nAChRs) are molecular targets of several anthelmintic drugs. Studies to date on Caenorhabditis elegans and Ascaris suum have demonstrated atypical pharmacology with respect to nAChR antagonists, including the finding that kappa-bungarotoxin is a more effective antagonist than alpha-bungarotoxin on Ascaris muscle nAChRs. Lophotoxin and its naturally occurring analogue bipinnatin B block all vertebrate and invertebrate nAChRs so far examined. In the present study, the effects on nematode nAChRs of bipinnatin B have been examined. The Ascaris suum muscle cell nAChR was found to be insensitive to 30 mumol l-1 bipinnatin B, a concentration that is highly effective on other nAChRs. To our knowledge, this is the first demonstration of a nAChR that is insensitive to one of the lophotoxins. Xenopus laevis oocytes injected with C. elegans polyadenylated, poly(A+), mRNA also expressed bipinnatin-B-insensitive levamisole responses, which were, however, blocked by the nAChR antagonist mecamylamine (10 mumol l-1). In contrast to the findings for nematode receptors, bipinnatin B (30 mumol l-1) was effective in blocking mouse muscle nAChRs expressed in Xenopus laevis oocytes and native insect nAChRs. A possible explanation for insensitivity of certain nematode nAChRs to lophotoxins is advanced based on the sequence of an alpha-like C. elegans nAChR subunit in which tyrosine-190 (numbering based on the Torpedo californica sequence), a residue known to be critical for lophotoxin binding in vertebrate nAChRs, is replaced by a proline residue.
ESTHER : Tornoe_1996_J.Exp.Biol_199_2161
PubMedSearch : Tornoe_1996_J.Exp.Biol_199_2161
PubMedID: 8896363

Title : Actions of neurotoxins (bungarotoxins, neosurugatoxin and lophotoxins) on insect and nematode nicotinic acetylcholine receptors - Tornoe_1995_Toxicon_33_411
Author(s) : Tornoe C , Bai D , Holden-Dye L , Abramson SN , Sattelle DB
Ref : Toxicon , 33 :411 , 1995
Abstract : Neurotoxins of natural origin have proved to be of considerable value in the isolation and characterization of vertebrate muscle and neuronal nicotinic acetylcholine receptors (nAChRs). To date, they have been used less extensively in studies of invertebrate nAChRs. Here we examine how a variety of neurotoxins (the snake toxins alpha-bungarotoxin, alpha-BGT, and kappa-bungarotoxin, kappa-BGT, the molluscan toxin, neosurugatoxin, and the soft coral toxins, lophotoxin and bipinnatin-B) can be used to characterize nAChRs in an insect, Periplaneta americana, and in a parasitic nematode, Ascaris suum. The agonist profiles of these nAChRs are distinct, but the most striking differences are in the actions of antagonists. Whereas the insect nAChR is blocked by both alpha- and kappa-bungarotoxins, the nematode receptor is only blocked by kappa-BGT. Neosurugatoxin blocks nAChRs in both species, but the lophotoxins which block all nAChRs investigated to date are much less effective on the Ascaris muscle receptor.
ESTHER : Tornoe_1995_Toxicon_33_411
PubMedSearch : Tornoe_1995_Toxicon_33_411
PubMedID: 7570627

Title : Actions of a coral toxin analogue (bipinnatin-B) on an insect nicotinic acetylcholine receptor - Bai_1993_Arch.Insect.Biochem.Physiol_23_155
Author(s) : Bai D , Abramson SN , Sattelle DB
Ref : Archives of Insect Biochemistry & Physiology , 23 :155 , 1993
Abstract : The lophotoxin analogue, bipinnatin-B, is a potent neurotoxin isolated from the gorgonian coral Pseudopterogorgia bipinnata. When tested on the cell body of an identified motor neurone, the fast coxal depressor motor neurone (Df) in the cockroach metathoracic ganglion, bipinnatin-B, at concentrations of 10 micronM,partially blocked nicotine-induced depolarization. Blockade of the response to nicotine was almost complete at 30 micronM bipinnatin-B, and was partially reversible on rebathing the preparation in normal saline. Responses of the same neurone to GABA were unaffected by 30 micronM bipinnatin-B.
ESTHER : Bai_1993_Arch.Insect.Biochem.Physiol_23_155
PubMedSearch : Bai_1993_Arch.Insect.Biochem.Physiol_23_155
PubMedID: 21313781

Title : Poster: Onchidal: a naturally occurring irreversible inhibitor of acetylcholinesterase with a novel mechanism of action -
Author(s) : Abramson SN , Radic Z , Manker D , Faulkner DJ , Taylor P
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :296 , 1991
PubMedID:

Title : Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations - Luetje_1990_J.Neurochem_55_632
Author(s) : Luetje CW , Wada K , Rogers S , Abramson SN , Tsuji K , Heinemann S , Patrick J
Ref : Journal of Neurochemistry , 55 :632 , 1990
Abstract : Neuronal and muscle nicotinic acetylcholine receptor subunit combinations expressed in Xenopus oocytes were tested for sensitivity to various neurotoxins. Extensive blockade of the alpha 3 beta 2 neuronal subunit combination was achieved by 10 nM neuronal bungarotoxin. Partial blockade of the alpha 4 beta 2 neuronal and alpha 1 beta 1 gamma delta muscle subunit combinations was caused by 1,000 nM neuronal bungarotoxin. The alpha 2 beta 2 neuronal subunit combination was insensitive to 1,000 nM neuronal bungarotoxin. Nearly complete blockade of all neuronal subunit combinations resulted from incubation with 2 nM neosurugatoxin, whereas 200 nM neosurugatoxin was required for partial blockade of the alpha 1 beta 1 gamma delta muscle subunit combination. The alpha 2 beta 2 and alpha 3 beta 2 neuronal subunit combinations were partially blocked by 10,000 nM lophotoxin analog-1, whereas complete blockade of the alpha 4 beta 2 neuronal and alpha 1 beta 1 gamma delta muscle subunit combinations resulted from incubation with this concentration of lophotoxin analog-1. The alpha 1 beta 1 gamma delta muscle subunit combination was blocked by the alpha-conotoxins G1A and M1 at concentrations of 100 nM. All of the neuronal subunit combinations were insensitive to 10,000 nM of both alpha-conotoxins. Thus, neosurugatoxin and the alpha-conotoxins distinguish between muscle and neuronal subunit combinations, whereas neuronal bungarotoxin and lophotoxin analog-1 distinguish between different neuronal subunit combinations on the basis of differing alpha subunits.
ESTHER : Luetje_1990_J.Neurochem_55_632
PubMedSearch : Luetje_1990_J.Neurochem_55_632
PubMedID: 1973456

Title : Studies on the topography of the catalytic site of acetylcholinesterase using polyclonal and monoclonal antibodies - Ogert_1990_J.Neurochem_55_756
Author(s) : Ogert RA , Gentry MK , Richardson EC , Deal CD , Abramson SN , Alving CR , Taylor P , Doctor BP
Ref : Journal of Neurochemistry , 55 :756 , 1990
Abstract : Polyclonal and monoclonal antibodies were generated against a synthetic peptide (25 amino acid residues) corresponding to the amino acid sequence surrounding the active site serine of Torpedo californica acetylcholinesterase (AChE). Prior to immunization, the peptide was either coupled to bovine serum albumin or encapsulated into liposomes containing lipid A as an adjuvant. To determine whether this region of AChE is located on the surface of the enzyme and thus accessible for binding to antibodies, or located in a pocket and thus not accessible to antibodies, the immunoreactivity of the antibodies was determined using enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, Western blots, and competition ELISA. The polyclonal antibody and several of the monoclonal antibodies failed to react with either Torpedo or fetal bovine serum AChE in their native conformations, but showed significant cross-reactivity with the denatured enzymes. Human serum butyrylcholinesterase, which has a high degree of amino acid sequence homology with these AChEs, failed to react with the same antibodies in either native form or denatured form. Chymotrypsin also failed to react with the monoclonal antibodies in either form. Eighteen octapeptides spanning the entire sequence of this region were synthesized on polyethylene pins, and epitopes of representative monoclonal antibodies were determined by ELISA. The reactivity of peptides suggest that a portion of the 25 mer peptide in AChE containing the active site serine is the primary epitope. It is not exposed on the surface of the enzyme and is most likely sequestered in a pocket-like conformation in the native enzyme.
ESTHER : Ogert_1990_J.Neurochem_55_756
PubMedSearch : Ogert_1990_J.Neurochem_55_756
PubMedID: 1696619

Title : Differences in structure and distribution of the molecular forms of acetylcholinesterase - Abramson_1989_J.Cell.Biol_108_2301
Author(s) : Abramson SN , Ellisman MH , Deerinck TJ , Maulet Y , Gentry MK , Doctor BP , Taylor P
Ref : Journal of Cell Biology , 108 :2301 , 1989
Abstract : Two structurally distinct molecular forms of acetylcholinesterase are found in the electric organs of Torpedo californica. One form is dimensionally asymmetric and composed of heterologous subunits. The other form is hydrophobic and composed of homologous subunits. Sequence-specific antibodies were raised against a synthetic peptide corresponding to the COOH-terminal region (Lys560-Leu575) of the catalytic subunits of the asymmetric form of acetylcholinesterase. These antibodies reacted with the asymmetric form of acetylcholinesterase, but not with the hydrophobic form. These results confirm recent studies suggesting that the COOH-terminal domain of the asymmetric form differs from that of the hydrophobic form, and represent the first demonstration of antibodies selective for the catalytic subunits of the asymmetric form. In addition, the reactive epitope of a monoclonal antibody (4E7), previously shown to be selective for the hydrophobic form of acetylcholinesterase, has been identified as an N-linked complex carbohydrate, thus defining posttranslational differences between the two forms. These two form-selective antibodies, as well as panselective polyclonal and monoclonal antibodies, were used in light and electron microscopic immunolocalization studies to investigate the distribution of the two forms of acetylcholinesterase in the electric organ of Torpedo. Both forms were localized almost exclusively to the innervated surface of the electrocytes. However, they were differentially distributed along the innervated surface. Specific asymmetric-form immunoreactivity was restricted to areas of synaptic apposition and to the invaginations of the postsynaptic membrane that form the synaptic gutters. In contrast, immunoreactivity attributable to the hydrophobic form was selectively found along the non-synaptic surface of the nerve terminals and was not observed in the synaptic cleft or in the invaginations of the postsynaptic membrane. This differential distribution suggests that the two forms of acetylcholinesterase may play different roles in regulating the local concentration of acetylcholine in the synapse.
ESTHER : Abramson_1989_J.Cell.Biol_108_2301
PubMedSearch : Abramson_1989_J.Cell.Biol_108_2301
PubMedID: 2472404

Title : Onchidal: a naturally occurring irreversible inhibitor of acetylcholinesterase with a novel mechanism of action - Abramson_1989_Mol.Pharmacol_36_349
Author(s) : Abramson SN , Radic Z , Manker D , Faulkner DJ , Taylor P
Ref : Molecular Pharmacology , 36 :349 , 1989
Abstract : Onchidal has been identified as the major lipid-soluble component of the defensive secretion of the mollusc Onchidella binneyi, and it has been proposed as the compound responsible for the chemical protection of Onchidella [Bioorg. Chem. 7:125-131 (1978)]. In support of this hypothesis, we now report that onchidal can be found in several different species of Onchidella and that it is toxic to fish. Because onchidal is an acetate ester similar to acetylcholine, its ability to interact with nicotinic acetylcholine receptors and acetylcholinesterase was investigated. Although onchidal did not prevent the binding of 125I-alpha-bungarotoxin to nicotinic acetylcholine receptors, it inhibited acetylcholinesterase in a progressive, apparently irreversible, manner. The apparent affinity of onchidal for the initial reversible binding to acetylcholinesterase (Kd) was approximately 300 microM, and the apparent rate constant for the subsequent irreversible inhibition of enzyme activity (kintact) was approximately 0.1 min-1. Onchidal was a substrate for acetylcholinesterase, and approximately 3250 mol of onchidal were hydrolyzed/mol of enzyme irreversibly inhibited. The calculated kcat for onchidal was 325 min-1. Irreversible inhibition resulted from either onchidal itself or a reactive intermediate in the enzyme-catalyzed hydrolysis of onchidal, rather than from the hydrolysis products of onchidal. Irreversible inhibition of enzyme activity was prevented by coincubation with reversible agents that either sterically block (edrophonium and decamethonium) or allosterically modify (propidium) the acetylcholine binding site. Enzyme activity was not regenerated by incubation with oxime reactivators; therefore, the mechanism of irreversible inhibition does not appear to involve acylation of the active site serine. Because onchidal contains a potentially reactive alpha,beta-unsaturated aldehyde, irreversible inhibition of acetylcholinesterase may result from formation of a novel covalent bond between the toxin and the enzyme. Thus, this novel toxin could potentially be exploited in the design of a new class of anticholinesterase insecticides and in the identification of amino acids that contribute to the binding and hydrolysis of acetylcholine.
ESTHER : Abramson_1989_Mol.Pharmacol_36_349
PubMedSearch : Abramson_1989_Mol.Pharmacol_36_349
PubMedID: 2779521