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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.
Biochem Pharmacol. 2011 Jan 15; 81(2):314-25.BP

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 (8850Da; 0.1-1μM) 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 (1-10nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA(2) 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 (125)I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pK(I)=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(33) 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)(2)βγδ nAChRs. This is probably as a result of an Arg(29) residue, previously shown to be critical for muscle (α1)(2)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.

Authors+Show Affiliations

Neurotoxin Research Group, Department of Medical & Molecular Biosciences, University of Technology, Sydney, P.O. Box 123, Broadway, NSW 2007, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20950587

Citation

Blacklow, Benjamin, et al. "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." Biochemical Pharmacology, vol. 81, no. 2, 2011, pp. 314-25.
Blacklow B, Kornhauser R, Hains PG, et al. 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. Biochem Pharmacol. 2011;81(2):314-25.
Blacklow, B., Kornhauser, R., Hains, P. G., Loiacono, R., Escoubas, P., Graudins, A., & Nicholson, G. M. (2011). 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. Biochemical Pharmacology, 81(2), 314-25. https://doi.org/10.1016/j.bcp.2010.10.004
Blacklow B, et al. 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. Biochem Pharmacol. 2011 Jan 15;81(2):314-25. PubMed PMID: 20950587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Blacklow,Benjamin, AU - Kornhauser,Rachelle, AU - Hains,Peter G, AU - Loiacono,Richard, AU - Escoubas,Pierre, AU - Graudins,Andis, AU - Nicholson,Graham M, Y1 - 2010/10/13/ PY - 2010/08/27/received PY - 2010/10/02/revised PY - 2010/10/05/accepted PY - 2010/10/19/entrez PY - 2010/10/19/pubmed PY - 2011/1/19/medline SP - 314 EP - 25 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 81 IS - 2 N2 - 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 (8850Da; 0.1-1μM) 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 (1-10nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA(2) 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 (125)I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pK(I)=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(33) 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)(2)βγδ nAChRs. This is probably as a result of an Arg(29) residue, previously shown to be critical for muscle (α1)(2)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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/20950587/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(10)00760-4 DB - PRIME DP - Unbound Medicine ER -