Venom Peptides From Cone Snails

Green, B R; Olivera, Baldomero M.

doi:10.1016/bs.ctm.2016.07.001

Cited by 27 publications

(14 citation statements)

References 52 publications

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“…M-superfamily toxins are highly diverse and are found in nearly all cone snail species studied to date where they are known to exert various functions [21]. Two well-studied classes within the M-superfamily are µ-conotoxins which target voltage-gated Na channels [31] and ψ-conotoxins which block muscle nAChR without competing with the bungarotoxin binding site [20]. While these toxins all belong to the M-superfamily and share the same cysteine framework with αM-MIIIJ, their primary amino acid sequences are highly divergent ( Figure 1A, bottom alignments).…”

Section: αM-miiij Uncovers a New Family Of Muscle Nachr-targeting Conmentioning

confidence: 99%

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

Rybin

O'Brien

Ramiro

et al. 2020

Toxins

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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.

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Section: αM-miiij Uncovers a New Family Of Muscle Nachr-targeting Conmentioning

confidence: 99%

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

Rybin

O'Brien

Ramiro

et al. 2020

Toxins

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“…These conotoxins have different mechanisms of action. Two classes (μ and μO) inhibit and two classes (δ and L) activate VGSCs ( Green and Olivera, 2016 ).…”

Section: Conotoxinsmentioning

confidence: 99%

Predicting Structural Details of the Sodium Channel Pore Basing on Animal Toxin Studies

Tikhonov

Zhorov

2018

Front. Pharmacol.

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Eukaryotic voltage-gated sodium channels play key roles in physiology and are targets for many toxins and medically important drugs. Physiology, pharmacology, and general architecture of the channels has long been the subject of intensive research in academia and industry. In particular, animal toxins such as tetrodotoxin, saxitoxin, and conotoxins have been used as molecular probes of the channel structure. More recently, X-ray structures of potassium and prokaryotic sodium channels allowed elaborating models of the toxin-channel complexes that integrated data from biophysical, electrophysiological, and mutational studies. Atomic level cryo-EM structures of eukaryotic sodium channels, which became available in 2017, show that the selectivity filter structure and other important features of the pore domain have been correctly predicted. This validates further employments of toxins and other small molecules as sensitive probes of fine structural details of ion channels.

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“…Its accurate characterization has shown a unique posttranslational modification and an odd number of cysteine residues in the primary amino acid sequence. Although the mechanism by which µO-GVIIJ may block the Nav channels is still to be clarified, it appears to be not a classical pore inhibitor [ 8 , 64 ].…”

Section: µ-Ctx Modulating Nav Currentsmentioning

confidence: 99%

“…Several CTX families have been identified to modulate Na + current, in particular μ- and μO-CTX are antagonist of the Nav channels. This specificity has been used to discriminate different Nav channel subtypes, characterize specific binding sites on the channels and elucidate the μ-CTX-Nav channel complex interaction [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential

2017

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The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of amino acids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µO-CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions.

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Venom Peptides From Cone Snails

Cited by 27 publications

References 52 publications

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

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

Predicting Structural Details of the Sodium Channel Pore Basing on Animal Toxin Studies

µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential

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