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The α9α10 Nicotinic Acetylcholine Receptor Antagonist αO-Conotoxin GeXIVA[1,2] Alleviates and Reverses Chemotherapy-Induced Neuropathic Pain
Open AccessFeature PaperArticle

Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi

1
Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O & N2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium
2
CSIR-National Institute of Oceanography, Dona Paula, Goa 403 004, India
3
Center of Advanced Study in Marine Biology, Annamalai University, Parangipettai, Tamil Nadu 608 502, India
4
Laboratory of Mass Spectrometry, Department of Chemistry, University of Liège, 4000 Liège, Belgium
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Mar. Drugs 2019, 17(9), 535; https://doi.org/10.3390/md17090535
Received: 29 July 2019 / Revised: 5 September 2019 / Accepted: 7 September 2019 / Published: 16 September 2019
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types. View Full-Text
Keywords: cone snail toxins; conopeptide; α-conotoxin; drug development; electrophysiology; ion channel diseases; nicotinic acetylcholine receptor cone snail toxins; conopeptide; α-conotoxin; drug development; electrophysiology; ion channel diseases; nicotinic acetylcholine receptor
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Peigneur, S.; Devi, P.; Seldeslachts, A.; Ravichandran, S.; Quinton, L.; Tytgat, J. Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi. Mar. Drugs 2019, 17, 535.

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