α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

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dc.contributor.author Blacklow, B
dc.contributor.author Kornhauser, R
dc.contributor.author Hains, PG
dc.contributor.author Loiacono, R
dc.contributor.author Escoubas, P
dc.contributor.author Graudins, A
dc.contributor.author Nicholson, GM
dc.date.accessioned 2012-10-12T03:33:26Z
dc.date.issued 2011-01-15
dc.identifier.citation Biochemical Pharmacology, 2011, 81 (2), pp. 314 - 325
dc.identifier.issn 0006-2952
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/18138
dc.description.abstract In contrast to all classical long-chain α-neurotoxins possessing the critical fifth disulfide bond, α-elapitoxin-Aa2a (α-EPTX-Aa2a), a novel long-chain α-neurotoxin from the common death adder Acanthophis antarcticus, lacks affinity for neuronal α7-type nicotinic acetylcholine receptors (nAChRs) α-EPTX-Aa2a (8850 Da; 0.1-1 μM) caused a concentration-dependent inhibition of indirect twitches, and blocked contractures to cholinergic agonists in the isolated chick biventer cervicis nerve-muscle preparation, consistent with a postsynaptic curaremimetic mode of action. α-EPTX-Aa2a (1-10 nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA2 value of 8.311 ± 0.031, which was not reversed by monovalent death adder antivenom. This is only 2.5-fold less potent than the prototypical long-chain α-neurotoxin, α-bungarotoxin. In contrast, α-EPTX-Aa2a produced complete, but weak, inhibition of 125I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pKI = 3.670), despite high sequence homology and similar mass to a wide range of long-chain α-neurotoxins. The mostly likely cause for the loss of α7 binding affinity is a leucine substitution, in loop II of α-EPTX-Aa2a, for the highly conserved Arg33 in long-chain α-neurotoxins. Arg 33 has been shown to be critical for both neuronal and muscle activity. Despite this substitution, α-EPTX-Aa2a retains high affinity for muscle (α1)2βγδ nAChRs. This is probably as a result of an Arg29 residue, previously shown to be critical for muscle (α1)2βγδ nAChR affinity, and highly conserved across all short-chain, but not long-chain, α-neurotoxins. α-EPTX-Aa2a therefore represents a novel atypical long-chain α-neurotoxin that includes a fifth disulfide but exhibits differential affinity for nAChR subtypes. Copyright © 2010 Published by Elsevier Inc. All rights reserved.
dc.language eng
dc.relation.hasversion Accepted Manuscript version en_US
dc.relation.isbasedon 10.1016/j.bcp.2010.10.004
dc.title α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors
dc.type Journal Article
dc.description.version Published
dc.parent Biochemical Pharmacology
dc.journal.volume 2
dc.journal.volume 81
dc.journal.number 2 en_US
dc.publocation Elsevier B.V. (Corporate Office) Radarweg 29, Amsterdam 1043 NX en_US
dc.identifier.startpage 314 en_US
dc.identifier.endpage 325 en_US
dc.cauo.name SCI.Faculty of Science en_US
dc.conference Verified OK en_US
dc.for 060110 Receptors and Membrane Biology
dc.for 111506 Toxicology (Incl. Clinical Toxicology)
dc.for 111501 Basic Pharmacology
dc.personcode 004814
dc.personcode 870145
dc.personcode 996649
dc.percentage 40 en_US
dc.classification.name Receptors and Membrane Biology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity en_US
dc.description.keywords α-Elapitoxin-Aa2a
dc.description.keywords Acanthophis antarcticus
dc.description.keywords Long-chain α-neurotoxin
dc.description.keywords Neuronal α7 receptor
dc.description.keywords Snake toxin
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - Health Technologies
utslib.copyright.status Open Access
utslib.copyright.date 2015-04-15 12:23:47.074767+10
pubs.consider-herdc true
utslib.collection.history General (ID: 2)


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