Characterisation of the heterotrimeric presynaptic phospholipase A2 neurotoxin complex from the venom of the common death adder (Acanthophis antarcticus)
Identifieur interne : 007A04 ( Main/Exploration ); précédent : 007A03; suivant : 007A05Characterisation of the heterotrimeric presynaptic phospholipase A2 neurotoxin complex from the venom of the common death adder (Acanthophis antarcticus)
Auteurs : Benjamin Blacklow [Australie] ; Pierre Escoubas [France] ; Graham M. Nicholson [Australie]Source :
- Biochemical pharmacology [ 0006-2952 ] ; 2010.
Descripteurs français
- Pascal (Inist)
- Wicri :
English descriptors
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Abstract
While Australo-Papuan death adder neurotoxicity is generally considered to be due to the actions of reversible competitive postsynaptic α-neurotoxins, the neurotoxic effects are often poorly reversed by antivenom or anticholinesterases. This suggests that the venom may contain a snake presynaptic phospholipase A2 (PLA2) neurotoxin (SPAN) that binds irreversibly to motor nerve terminals to inhibit neurotransmitter release. Using size-exclusion liquid chromatography under non-reducing conditions, we report the isolation and characterisation of a high molecular mass SPAN complex, P-elapitoxin-Aa1a (P-EPTX-Aa1a), from the venom of the common death adder Acanthophis antarcticus. Using the chick biventer-cervicis nerve-muscle preparation, P-EPTX-Aa1a (44,698 Da) caused inhibition of nerve-evoked twitch contractions while responses to cholinergic agonists and KCl remained unaffected. P-EPTX-Aa1a also produced significant fade in tetanic contractions and a triphasic timecourse of neuromuscular blockade. These actions are consistent with other SPANs that inhibit acetylcholine release. P-EPTX-Aa1a was found to be a heterotrimeric complex composed of α, β and γ-subunits in a 1:1:1 stoichiometry with each subunit showing significant N-terminal sequence homology to the subunits of taipoxin, a SPAN from Oxyuranus s. scutellatus. Like taipoxin, only the α-chain produced any signs of neurotoxicity or displayed significant PLA2 enzymatic activity. Preincubation with monovalent death adder antivenom or suramin, or inhibition of PLA2 activity by incubation with 4-bromophenacyl bromide, either prevented or significantly delayed the onset of toxicity by P-EPTX-Aa1a. However, antivenom failed to reverse neurotoxicity. Early intervention with antivenom may therefore be important in severe cases of envenomation by A. antarcticus, given the presence of potent irreversible presynaptic neurotoxins.
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Nicholson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurotoxin Research Group, Department of Medical & Molecular Biosciences, University of Technology, Sydney, P.O. 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Box 123</s1><s2>Broadway, NSW 2007</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Broadway, NSW 2007</wicri:noRegion></affiliation></author><author><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Université de Nice - Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR6097, 660 Route des Lucioles</s1><s2>06560 Valbonne</s2><s3>FRA</s3><sZ>2 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>06560 Valbonne</wicri:noRegion><wicri:noRegion>660 Route des Lucioles</wicri:noRegion><wicri:noRegion>06560 Valbonne</wicri:noRegion><orgName type="university">Université Nice Sophia Antipolis</orgName><placeName><settlement type="city">Nice</settlement><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region></placeName></affiliation></author><author><name sortKey="Nicholson, Graham M" sort="Nicholson, Graham M" uniqKey="Nicholson G" first="Graham M." last="Nicholson">Graham M. Nicholson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurotoxin Research Group, Department of Medical & Molecular Biosciences, University of Technology, Sydney, P.O. Box 123</s1><s2>Broadway, NSW 2007</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Broadway, NSW 2007</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal origin</term><term>Death</term><term>Mortality</term><term>Neurotoxin</term><term>Ophidia</term><term>Presynaptic</term><term>Venom</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Présynaptique</term><term>Neurotoxine</term><term>Venin</term><term>Origine animale</term><term>Mort</term><term>Mortalité</term><term>Ophidia</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Mort</term><term>Mortalité</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">While Australo-Papuan death adder neurotoxicity is generally considered to be due to the actions of reversible competitive postsynaptic α-neurotoxins, the neurotoxic effects are often poorly reversed by antivenom or anticholinesterases. This suggests that the venom may contain a snake presynaptic phospholipase A<sub>2</sub> (PLA<sub>2</sub>) neurotoxin (SPAN) that binds irreversibly to motor nerve terminals to inhibit neurotransmitter release. Using size-exclusion liquid chromatography under non-reducing conditions, we report the isolation and characterisation of a high molecular mass SPAN complex, P-elapitoxin-Aa1a (P-EPTX-Aa1a), from the venom of the common death adder Acanthophis antarcticus. Using the chick biventer-cervicis nerve-muscle preparation, P-EPTX-Aa1a (44,698 Da) caused inhibition of nerve-evoked twitch contractions while responses to cholinergic agonists and KCl remained unaffected. P-EPTX-Aa1a also produced significant fade in tetanic contractions and a triphasic timecourse of neuromuscular blockade. These actions are consistent with other SPANs that inhibit acetylcholine release. P-EPTX-Aa1a was found to be a heterotrimeric complex composed of α, β and γ-subunits in a 1:1:1 stoichiometry with each subunit showing significant N-terminal sequence homology to the subunits of taipoxin, a SPAN from Oxyuranus s. scutellatus. Like taipoxin, only the α-chain produced any signs of neurotoxicity or displayed significant PLA<sub>2</sub> enzymatic activity. Preincubation with monovalent death adder antivenom or suramin, or inhibition of PLA<sub>2</sub> activity by incubation with 4-bromophenacyl bromide, either prevented or significantly delayed the onset of toxicity by P-EPTX-Aa1a. However, antivenom failed to reverse neurotoxicity. Early intervention with antivenom may therefore be important in severe cases of envenomation by A. antarcticus, given the presence of potent irreversible presynaptic neurotoxins.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Provence-Alpes-Côte d'Azur</li></region><settlement><li>Nice</li></settlement><orgName><li>Université Nice Sophia Antipolis</li></orgName></list><tree><country name="Australie"><noRegion><name sortKey="Blacklow, Benjamin" sort="Blacklow, Benjamin" uniqKey="Blacklow B" first="Benjamin" last="Blacklow">Benjamin Blacklow</name></noRegion><name sortKey="Nicholson, Graham M" sort="Nicholson, Graham M" uniqKey="Nicholson G" first="Graham M." last="Nicholson">Graham M. Nicholson</name></country><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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