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Article

αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish

by
Matthew J. Rybin
1,2,
Henrik O’Brien
1,
Iris Bea L. Ramiro
1,3,
Layla Azam
1,
J. Michael McIntosh
1,4,5,
Baldomero M. Olivera
1,
Helena Safavi-Hemami
1,3,6,* and
Doju Yoshikami
1,*
1
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA
2
Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
3
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
4
George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT 84112, USA
5
Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA
6
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
*
Authors to whom correspondence should be addressed.
Toxins 2020, 12(3), 197; https://doi.org/10.3390/toxins12030197
Submission received: 22 February 2020 / Revised: 17 March 2020 / Accepted: 18 March 2020 / Published: 21 March 2020
(This article belongs to the Section Animal Venoms)
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Abstract

We report the discovery and functional characterization of αM-Conotoxin MIIIJ, a peptide from the venom of the fish-hunting cone snail Conus magus. Injections of αM-MIIIJ induced paralysis in goldfish (Carassius auratus) but not mice. Intracellular recording from skeletal muscles of fish (C. auratus) and frog (Xenopus laevis) revealed that αM-MIIIJ inhibited postsynaptic nicotinic acetylcholine receptors (nAChRs) with an IC50 of ~0.1 μM. With comparable potency, αM-MIIIJ reversibly blocked ACh-gated currents (IACh) of voltage-clamped X. laevis oocytes exogenously expressing nAChRs cloned from zebrafish (Danio rerio) muscle. αM-MIIIJ also protected against slowly-reversible block of IACh by α-bungarotoxin (α-BgTX, a snake neurotoxin) and α-conotoxin EI (α-EI, from Conus ermineus another fish hunter) that competitively block nAChRs at the ACh binding site. Furthermore, assessment by fluorescence microscopy showed that αM-MIIIJ inhibited the binding of fluorescently-tagged α-BgTX at neuromuscular junctions of X. laevis, C. auratus, and D. rerio. (Note, we observed that αM-MIIIJ can block adult mouse and human muscle nAChRs exogenously expressed in X. laevis oocytes, but with IC50s ~100-times higher than those of zebrafish nAChRs.) Taken together, these results indicate that αM-MIIIJ inhibits muscle nAChRs and furthermore apparently does so by interfering with the binding of ACh to its receptor. Comparative alignments with homologous sequences identified in other fish hunters revealed that αM-MIIIJ defines a new class of muscle nAChR inhibitors from cone snails.
Keywords: venom; conotoxin; nicotinic acetylcholine receptor; neuromuscular junction venom; conotoxin; nicotinic acetylcholine receptor; neuromuscular junction

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MDPI and ACS Style

Rybin, M.J.; O’Brien, H.; Ramiro, I.B.L.; Azam, L.; McIntosh, J.M.; Olivera, B.M.; Safavi-Hemami, H.; Yoshikami, D. αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish. Toxins 2020, 12, 197. https://doi.org/10.3390/toxins12030197

AMA Style

Rybin MJ, O’Brien H, Ramiro IBL, Azam L, McIntosh JM, Olivera BM, Safavi-Hemami H, Yoshikami D. αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish. Toxins. 2020; 12(3):197. https://doi.org/10.3390/toxins12030197

Chicago/Turabian Style

Rybin, Matthew J., Henrik O’Brien, Iris Bea L. Ramiro, Layla Azam, J. Michael McIntosh, Baldomero M. Olivera, Helena Safavi-Hemami, and Doju Yoshikami. 2020. "αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish" Toxins 12, no. 3: 197. https://doi.org/10.3390/toxins12030197

APA Style

Rybin, M. J., O’Brien, H., Ramiro, I. B. L., Azam, L., McIntosh, J. M., Olivera, B. M., Safavi-Hemami, H., & Yoshikami, D. (2020). αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish. Toxins, 12(3), 197. https://doi.org/10.3390/toxins12030197

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