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Mar. Drugs 2017, 15(6), 170;

Identification of a Novel O-Conotoxin Reveals an Unusual and Potent Inhibitor of the Human α9α10 Nicotinic Acetylcholine Receptor

Department of Central Laboratory, Shanghai 10th People’s Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
Authors to whom correspondence should be addressed.
Academic Editor: Keith B. Glaser
Received: 5 April 2017 / Revised: 30 May 2017 / Accepted: 6 June 2017 / Published: 9 June 2017
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Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human α9α10 nicotinic acetylcholine receptor (nAChR), with an IC50 of 16.2 ± 1.4 nM. The activities of the N-terminal and C-terminal halves of the linear toxin are markedly reduced compared with the full-length toxin, suggesting that the intact sequence is required to potently inhibit the hα9α10 nAChR. α9α10 nAChRs are expressed not only in the nervous system, but also in a variety of non-neuronal cells, such as cochlear hair cells, keratinocytes, epithelial and immune cells. A potent inhibitor of human α9α10 nAChRs, such as GeXXVIIA, would facilitate unraveling the functions of this nAChR subtype. Furthermore, this unusual nAChR inhibitor may lead to the development of novel α9α10 nAChR-targeting drugs. View Full-Text
Keywords: conotoxin; O-superfamily; nicotinic receptor; α9α10; linear peptide conotoxin; O-superfamily; nicotinic receptor; α9α10; linear peptide

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Jiang, S.; Tae, H.-S.; Xu, S.; Shao, X.; Adams, D.J.; Wang, C. Identification of a Novel O-Conotoxin Reveals an Unusual and Potent Inhibitor of the Human α9α10 Nicotinic Acetylcholine Receptor. Mar. Drugs 2017, 15, 170.

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