alpha M-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish
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alpha M-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish. / Rybin, Matthew J.; O'Brien, Henrik; Ramiro, Iris Bea L.; Azam, Layla; McIntosh, J. Michael; Olivera, Baldomero M.; Safavi-Hemami, Helena; Yoshikami, Doju.
I: Toxins, Bind 12, Nr. 3, 197, 2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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TY - JOUR
T1 - alpha M-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish
AU - Rybin, Matthew J.
AU - O'Brien, Henrik
AU - Ramiro, Iris Bea L.
AU - Azam, Layla
AU - McIntosh, J. Michael
AU - Olivera, Baldomero M.
AU - Safavi-Hemami, Helena
AU - Yoshikami, Doju
PY - 2020
Y1 - 2020
N2 - We report the discovery and functional characterization of alpha M-Conotoxin MIIIJ, a peptide from the venom of the fish-hunting cone snail Conus magus. Injections of alpha M-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 alpha M-MIIIJ inhibited postsynaptic nicotinic acetylcholine receptors (nAChRs) with an IC50 of similar to 0.1 mu M. With comparable potency, alpha M-MIIIJ reversibly blocked ACh-gated currents (I-ACh) of voltage-clamped X. laevis oocytes exogenously expressing nAChRs cloned from zebrafish (Danio rerio) muscle. alpha M-MIIIJ also protected against slowly-reversible block of I-ACh by alpha-bungarotoxin (alpha-BgTX, a snake neurotoxin) and alpha-conotoxin EI (alpha-EI, from Conus ermineus another fish hunter) that competitively block nAChRs at the ACh binding site. Furthermore, assessment by fluorescence microscopy showed that alpha M-MIIIJ inhibited the binding of fluorescently-tagged alpha-BgTX at neuromuscular junctions of X. laevis, C. auratus, and D. rerio. (Note, we observed that alpha M-MIIIJ can block adult mouse and human muscle nAChRs exogenously expressed in X. laevis oocytes, but with IC(50)s similar to 100-times higher than those of zebrafish nAChRs.) Taken together, these results indicate that alpha M-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 alpha M-MIIIJ defines a new class of muscle nAChR inhibitors from cone snails.
AB - We report the discovery and functional characterization of alpha M-Conotoxin MIIIJ, a peptide from the venom of the fish-hunting cone snail Conus magus. Injections of alpha M-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 alpha M-MIIIJ inhibited postsynaptic nicotinic acetylcholine receptors (nAChRs) with an IC50 of similar to 0.1 mu M. With comparable potency, alpha M-MIIIJ reversibly blocked ACh-gated currents (I-ACh) of voltage-clamped X. laevis oocytes exogenously expressing nAChRs cloned from zebrafish (Danio rerio) muscle. alpha M-MIIIJ also protected against slowly-reversible block of I-ACh by alpha-bungarotoxin (alpha-BgTX, a snake neurotoxin) and alpha-conotoxin EI (alpha-EI, from Conus ermineus another fish hunter) that competitively block nAChRs at the ACh binding site. Furthermore, assessment by fluorescence microscopy showed that alpha M-MIIIJ inhibited the binding of fluorescently-tagged alpha-BgTX at neuromuscular junctions of X. laevis, C. auratus, and D. rerio. (Note, we observed that alpha M-MIIIJ can block adult mouse and human muscle nAChRs exogenously expressed in X. laevis oocytes, but with IC(50)s similar to 100-times higher than those of zebrafish nAChRs.) Taken together, these results indicate that alpha M-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 alpha M-MIIIJ defines a new class of muscle nAChR inhibitors from cone snails.
KW - venom
KW - conotoxin
KW - nicotinic acetylcholine receptor
KW - neuromuscular junction
KW - SODIUM-CHANNELS
KW - CONUS-GEOGRAPHUS
KW - PREFERENTIAL INHIBITION
KW - OMEGA-CONOTOXIN
KW - SKELETAL-MUSCLE
KW - VENOM PEPTIDES
KW - PSI-CONOTOXIN
KW - TRANSMISSION
KW - ANTAGONIST
KW - TARGETS
U2 - 10.3390/toxins12030197
DO - 10.3390/toxins12030197
M3 - Journal article
C2 - 32245200
VL - 12
JO - Toxins
JF - Toxins
SN - 2072-6651
IS - 3
M1 - 197
ER -
ID: 247214465