AustralieFrV1, Main, Exploration, bibRecord, 006543

α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α-1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

Identifieur interne : 006543 ( Main/Exploration ); précédent : 006542; suivant : 006544

α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α-1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

Auteurs : Benjamin Blacklow [Australie] ; Rachelle Kornhauser [Australie] ; Peter G. Hains [Australie] ; Richard Loiacono [Australie] ; Pierre Escoubas [France] ; Andis Graudins [Australie] ; Graham M. Nicholson [Australie]

Source :

Biochemical pharmacology [ 0006-2952 ] ; 2011.

RBID : Pascal:11-0085326

Descripteurs français

Pascal (Inist)
- Chaîne longue, Chaîne peptidique α, Ophidia, Neurotoxine, Muscle, Récepteur nicotinique, Affinité, Neurone, Récepteur nicotinique α7, Récepteur biologique.

English descriptors

KwdEn :
- Affinity, Alpha-Peptide chain, Biological receptor, Long chain, Muscle, Neuron, Neurotoxin, Nicotinic receptor, Ophidia, α7 nicotinic receptor.

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 ¹¹⁵I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pK₁ = 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. Arg³³ 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.

Affiliations:

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Le document en format XML

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βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors</title>
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βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors</title>
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<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Université de Nice Sophia Antipolis, CNRS UMR6097, 660 Route des Lucioles</s1>
<s2>06560 Valbonne</s2>
<s3>FRA</s3>
<sZ>5 aut.</sZ>
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<wicri:noRegion>660 Route des Lucioles</wicri:noRegion>
<wicri:noRegion>06560 Valbonne</wicri:noRegion>
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</author>
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<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Emergency Medicine, Prince of Wales Hospital</s1>
<s2>Randwick 2031</s2>
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<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>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Affinity</term>
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<front><div type="abstract" xml:lang="en">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 pA<sub>2</sub>
 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 <sup>115</sup>
I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pK<sub>1</sub>
 = 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 Arg<sup>33</sup>
 in long-chain α-neurotoxins. Arg<sup>33</sup>
 has been shown to be critical for both neuronal and muscle activity. Despite this substitution, α-EPTX-Aa2a retains high affinity for muscle (α1)<sub>2</sub>
βγδ nAChRs. This is probably as a result of an Arg<sup>29</sup>
 residue, previously shown to be critical for muscle (α1)<sub>2</sub>
βγδ 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.</div>
</front>
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<name sortKey="Hains, Peter G" sort="Hains, Peter G" uniqKey="Hains P" first="Peter G." last="Hains">Peter G. Hains</name>
<name sortKey="Kornhauser, Rachelle" sort="Kornhauser, Rachelle" uniqKey="Kornhauser R" first="Rachelle" last="Kornhauser">Rachelle Kornhauser</name>
<name sortKey="Loiacono, Richard" sort="Loiacono, Richard" uniqKey="Loiacono R" first="Richard" last="Loiacono">Richard Loiacono</name>
<name sortKey="Nicholson, Graham M" sort="Nicholson, Graham M" uniqKey="Nicholson G" first="Graham M." last="Nicholson">Graham M. Nicholson</name>
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<country name="France"><noRegion><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name>
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α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α-1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α-1)2βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri