α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors
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-E...
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ftunivtsydney:oai:opus.lib.uts.edu.au:10453/18138 2023-05-15T13:54:43+02:00 α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors Blacklow, B Kornhauser, R Hains, PG Loiacono, R Escoubas, P Graudins, A Nicholson, GM 2011-01-15 application/pdf http://hdl.handle.net/10453/18138 unknown Biochemical Pharmacology 10.1016/j.bcp.2010.10.004 Biochemical Pharmacology, 2011, 81 (2), pp. 314 - 325 0006-2952 http://hdl.handle.net/10453/18138 Pharmacology & Pharmacy Muscle Skeletal Neurons Animals Rats Sprague-Dawley Elapidae Carbachol Receptors Nicotinic Elapid Venoms Neurotoxins Dose-Response Relationship Drug Female Phospholipases A2 Journal Article 2011 ftunivtsydney 2022-03-13T13:26:24Z 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. Article in Journal/Newspaper Antarc* antarcticus University of Technology Sydney: OPUS - Open Publications of UTS Scholars |
institution |
Open Polar |
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University of Technology Sydney: OPUS - Open Publications of UTS Scholars |
op_collection_id |
ftunivtsydney |
language |
unknown |
topic |
Pharmacology & Pharmacy Muscle Skeletal Neurons Animals Rats Sprague-Dawley Elapidae Carbachol Receptors Nicotinic Elapid Venoms Neurotoxins Dose-Response Relationship Drug Female Phospholipases A2 |
spellingShingle |
Pharmacology & Pharmacy Muscle Skeletal Neurons Animals Rats Sprague-Dawley Elapidae Carbachol Receptors Nicotinic Elapid Venoms Neurotoxins Dose-Response Relationship Drug Female Phospholipases A2 Blacklow, B Kornhauser, R Hains, PG Loiacono, R Escoubas, P Graudins, A Nicholson, GM α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
topic_facet |
Pharmacology & Pharmacy Muscle Skeletal Neurons Animals Rats Sprague-Dawley Elapidae Carbachol Receptors Nicotinic Elapid Venoms Neurotoxins Dose-Response Relationship Drug Female Phospholipases A2 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Blacklow, B Kornhauser, R Hains, PG Loiacono, R Escoubas, P Graudins, A Nicholson, GM |
author_facet |
Blacklow, B Kornhauser, R Hains, PG Loiacono, R Escoubas, P Graudins, A Nicholson, GM |
author_sort |
Blacklow, B |
title |
α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
title_short |
α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
title_full |
α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
title_fullStr |
α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
title_full_unstemmed |
α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
title_sort |
α-elapitoxin-aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1) 2 βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors |
publishDate |
2011 |
url |
http://hdl.handle.net/10453/18138 |
genre |
Antarc* antarcticus |
genre_facet |
Antarc* antarcticus |
op_relation |
Biochemical Pharmacology 10.1016/j.bcp.2010.10.004 Biochemical Pharmacology, 2011, 81 (2), pp. 314 - 325 0006-2952 http://hdl.handle.net/10453/18138 |
_version_ |
1766260793951649792 |