Conotoxin modulation of voltage-gated sodium channels (original) (raw)
Related papers
Conotoxins targeting neuronal voltage-gated sodium channel subtypes: Potential analgesics?
2012
Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: μ-, μO-, δ-and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the μ-and μO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the μ-and μO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.
µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential
Marine Drugs
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.
µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission
2017
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 aminoacids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µ-O 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. Hyperxcitability 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 manage...
1 μ-Conotoxins Modulating Sodium Currents in Pain 2 Perception and Transmission 3
2017
The Conus genus includes around 500 species of marine mollusks with a peculiar 9 production of venomous peptides known as conotoxins (CTX). Each species is able to produce up 10 to 200 different biological active peptides. Common structure of CTX is the low number of 11 aminoacids stabilized by disulfide bridges and post-translational modifications that give rise to 12 different isoforms. μ and μO-CTX are two isoforms that specifically target voltage-gated sodium 13 channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal 14 excitability by depolarizing plasma membrane and propagating the action potential. 15 Hyperxcitability and mutations of sodium channels are responsible for perception and transmission 16 of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of 17 μ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their 18 potential therapeutic use as analgesic comp...
µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission
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 aminoacids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µ-O 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. Hyperxcitability 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 t...
Sodium channel modulating activity in a δ-conotoxin from an Indian marine snail
Febs Letters, 2003
A 26 residue peptide (Am 2766) with the sequence CKQAGESCDIFSQNCCVG-TCAFICIE-NH 2 has been isolated and puri¢ed from the venom of the molluscivorous snail, Conus amadis, collected o¡ the southeastern coast of India. Chemical modi¢cation and mass spectrometric studies establish that Am 2766 has three disul¢de bridges. C-terminal amidation has been demonstrated by mass measurements on the C-terminal fragments obtained by proteolysis. Sequence alignments establish that Am 2766 belongs to the N N-conotoxin family. Am 2766 inhibits the decay of the sodium current in brain rNav1.2a voltage-gated Na + channel, stably expressed in Chinese hamster ovary cells. Unlike N N-conotoxins have previously been isolated from molluscivorous snails, Am 2766 inhibits inactivation of mammalian sodium channels. ß
Biochemistry, 2002
µ-Conotoxins are a family of peptides from the venoms of predatory cone snails. Previously characterized µ-conotoxins preferentially block skeletal muscle voltage-gated sodium channels. We report here the discovery (via cloning), synthesis, and electrophysiological characterization of a new peptide in this family, µ-conotoxin SmIIIA from Conus stercusmuscarum. Although µ-conotoxin SmIIIA shares several biochemical characteristics with other µ-conotoxins (the arrangement of cysteine residues and a conserved arginine believed to interact with residues near the channel pore), it has distinctive features such as the absence of hydroxyproline. In voltage-clamped dissociated neurons from frog sympathetic and dorsal root ganglia, the peptide inhibited the majority of tetrodotoxin-resistant sodium currents irreversibly; in contrast, tetrodotoxin-sensitive sodium currents were largely unaffected by the peptide. We believe that µ-conotoxin SmIIIA is the first specific antagonist of tetrodotoxin-resistant voltage-gated sodium channels to be discovered. Thus, the peptide provides a new and potentially useful tool to investigate the functional roles of tetrodotoxin-resistant voltage-gated sodium channels, including those that are found in sensory nerves that convey nociceptive information.
Journal of Biological Chemistry, 2007
4 The abbreviations used are: TTX-r, tetrodotoxin-resistant; TTX-s, TTXsensitive; DRG, dorsal root ganglion; Na V , voltage-gated sodium channel; KIIIA,-conotoxin KIIIA; mNa V , Na V cloned from mouse; rNa V , Na V cloned from rat; Fmoc, N-(9-fluorenyl)methoxycarbonyl; HPLC, high pressure liquid chromatography; MOPS, 4-morpholinepropanesulfonic acid.
Proceedings of the National Academy of Sciences, 2011
Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing α-subunit (Na V 1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na V 1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 μ-conopeptides for their ability to block rodent Na V 1.1 through 1.8 expressed in Xenopus oocytes. Although none blocked Na V 1.8, a TTX-resistant isoform, the resulting “activity matrix” revealed that the panel could readily discriminate between the members of all pair-wise combinations of the tested isoforms. To examine the identities of endogenous VGSCs, a subset of the panel was tested on A- and C-compound action potentials recorded from isolated preparations of rat sciatic nerve. The results show that the major subtypes ...
Molecular interaction of δ-conotoxins with voltage-gated sodium channels
Febs Letters, 2005
Various neurotoxic peptides modulate voltage-gated sodium (Na V ) channels and thereby affect cellular excitability. d-Conotoxins from predatory cone snails slow down inactivation of Na V channels, but their interaction site and mechanism of channel modulation are unknown. Here, we show that d-conotoxin SVIE from Conus striatus interacts with a conserved hydrophobic triad (YFV) in the domain-4 voltage sensor of Na V channels. This site overlaps with that of the scorpion a-toxin Lqh-2, but not with the a-like toxin Lqh-3 site. d-SVIE functionally competes with Lqh-2, but exhibits strong cooperativity with Lqh-3, presumably by synergistically trapping the voltage sensor in its ''on'' position.