Alpha-Elapitoxin-Aa2a, a long-chain snake alpha-neurotoxin with potent actions on muscle (alpha1)2betagammadelta nicotinic receptors, lacks the classical high affinity for neuronal alpha7 nicotinic receptors

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dc.contributor.author Blacklow, Benjamin en_US
dc.contributor.author Kornhauser, Rachelle en_US
dc.contributor.author Hains, Peter en_US
dc.contributor.author Loiacono, Richard en_US
dc.contributor.author Escoubas, Pierre en_US
dc.contributor.author Graudins, Andis en_US
dc.contributor.author Nicholson, Graham en_US
dc.contributor.editor en_US
dc.date.accessioned 2012-10-12T03:33:26Z
dc.date.available 2012-10-12T03:33:26Z
dc.date.issued 2011 en_US
dc.identifier 2009007729 en_US
dc.identifier.citation Blacklow Benjamin et al. 2011, 'Alpha-Elapitoxin-Aa2a, a long-chain snake alpha-neurotoxin with potent actions on muscle (alpha1)2betagammadelta nicotinic receptors, lacks the classical high affinity for neuronal alpha7 nicotinic receptors', Elsevier, vol. 81, no. 2, pp. 314-325. en_US
dc.identifier.issn 0006-2952 en_US
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 alpha-neurotoxins possessing the critical fifth disulfide bond, alpha-elapitoxin-Aa2a (alpha-EPTX-Aa2a), a novel long-chain alpha-neurotoxin from the common death adder Acanthophis antarcticus, lacks affinity for neuronal alpha7-type nicotinic acetylcholine receptors (nAChRs). alpha-EPTX-Aa2a (8850 Da; 0.1-1 microM) 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. alpha-EPTX-Aa2a (1-10 nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA2 value of 8.311 A? 0.031, which was not reversed by monovalent death adder antivenom. This is only 2.5-fold less potent than the prototypical long-chain alpha-neurotoxin, alpha-bungarotoxin. In contrast, alpha-EPTX-Aa2a produced complete, but weak, inhibition of 125I-alpha-bungarotoxin binding to rat hippocampal a7 nAChRs (pKI = 3.670), despite high sequence homology and similar mass to a wide range of long-chain alpha-neurotoxins. The mostly likely cause for the loss of alpha7 binding affinity is a leucine substitution, in loop II of alpha-EPTX-Aa2a, for the highly conserved Arg33 in long-chain alpha-neurotoxins. Arg33 has been shown to be critical for both neuronal and muscle activity. Despite this substitution, alpha-EPTX-Aa2a retains high affinity for muscle (alpha1)2betagammadelta nAChRs. This is probably as a result of an Arg29 residue, previously shown to be critical for muscle (alpha1)2betagammadelta nAChR affinity, and highly conserved across all short-chain, but not long-chain, alpha-neurotoxins. alpha-EPTX-Aa2a therefore represents a novel atypical long-chain alpha-neurotoxin that includes a fifth disulfide but exhibits differential affinity for nAChR subtypes. en_US
dc.language en_US
dc.publisher Elsevier en_US
dc.relation.hasversion Accepted Manuscript version en_US
dc.relation.isbasedon http://dx.doi.org/10.1016/j.bcp.2010.10.004 en_US
dc.rights NOTICE: this is the author’s version of a work that was accepted for publication in Biochemical Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochemical Pharmacology, [Volume 81, Issue 2, 15 January 2011, Pages 314–325] DOI#” http://dx.doi.org/10.1016/j.bcp.2010.10.004 en_US
dc.title Alpha-Elapitoxin-Aa2a, a long-chain snake alpha-neurotoxin with potent actions on muscle (alpha1)2betagammadelta nicotinic receptors, lacks the classical high affinity for neuronal alpha7 nicotinic receptors en_US
dc.parent Biochemical Pharmacology en_US
dc.journal.volume 81 en_US
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 en_US
dc.personcode 996649 en_US
dc.personcode 0000063947 en_US
dc.personcode 0000063946 en_US
dc.personcode 0000063948 en_US
dc.personcode 0000023295 en_US
dc.personcode 004814 en_US
dc.personcode 870145 en_US
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 Snake toxin Long-chain a-neurotoxin a-Elapitoxin-Aa2a Acanthophis antarcticus Neuronal a7 receptor en_US
dc.staffid 870145 en_US


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