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A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors.
Favreau P, Benoit E, Hocking HG, Carlier L, D' hoedt D, Leipold E, Markgraf R, Schlumberger S, Córdova MA, Gaertner H, Paolini-Bertrand M, Hartley O, Tytgat J, Heinemann SH, Bertrand D, Boelens R, Stöcklin R, Molgó J.
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The µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant.µ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data.Synthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC(50) = 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked Na(V)1.4 (IC(50) = 1.3 nM) and Na(V)1.2 channels in a long-lasting manner. Cardiac Na(V)1.5 and DRG-specific Na(V)1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the α3β2 nAChR subtype (IC(50) = 450 nM) and, to a lesser extent, on the α7 and α4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to α-conotoxins acting on nAChRs.µ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels.
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed Brünger,
Crystallography & NMR system: A new software suite for macromolecular structure determination.
1998,
Pubmed Buczek,
Conotoxins and the posttranslational modification of secreted gene products.
2005,
Pubmed Bulaj,
Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels.
2005,
Pubmed Caldwell,
Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses.
2000,
Pubmed Cartier,
A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors.
1996,
Pubmed
,
Xenbase Chen,
Modulation of cloned skeletal muscle sodium channels by the scorpion toxins Lqh II, Lqh III, and Lqh alphaIT.
2000,
Pubmed Cruz,
Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
1985,
Pubmed Edgerton,
Inhibition of the activation pathway of the T-type calcium channel Ca(V)3.1 by ProTxII.
2010,
Pubmed Ekberg,
Conotoxin modulation of voltage-gated sodium channels.
2008,
Pubmed Fainzilber,
New sodium channel-blocking conotoxins also affect calcium currents in Lymnaea neurons.
1995,
Pubmed Favreau,
Marine snail venoms: use and trends in receptor and channel neuropharmacology.
2009,
Pubmed Halai,
Conotoxins: natural product drug leads.
2009,
Pubmed Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed Han,
Structurally minimized mu-conotoxin analogues as sodium channel blockers: implications for designing conopeptide-based therapeutics.
2009,
Pubmed
,
Xenbase Herrero,
Differential blockade of rat alpha3beta4 and alpha7 neuronal nicotinic receptors by omega-conotoxin MVIIC, omega-conotoxin GVIA and diltiazem.
1999,
Pubmed
,
Xenbase Herrmann,
Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA.
2002,
Pubmed Hill,
Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels.
1996,
Pubmed Hogg,
An automated system for intracellular and intranuclear injection.
2008,
Pubmed
,
Xenbase Holford,
Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus.
2009,
Pubmed
,
Xenbase Imperial,
A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins.
2006,
Pubmed Keizer,
Structural basis for tetrodotoxin-resistant sodium channel binding by mu-conotoxin SmIIIA.
2003,
Pubmed Khoo,
Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion.
2009,
Pubmed
,
Xenbase Klimis,
A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain.
2011,
Pubmed Kumar,
A two-dimensional nuclear Overhauser enhancement (2D NOE) experiment for the elucidation of complete proton-proton cross-relaxation networks in biological macromolecules.
1980,
Pubmed Lewis,
Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels.
2007,
Pubmed
,
Xenbase Li,
Using the deadly mu-conotoxins as probes of voltage-gated sodium channels.
2004,
Pubmed Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Lluisma,
Characterization of a novel psi-conotoxin from Conus parius Reeve.
2008,
Pubmed
,
Xenbase Lopez-Vera,
Role of hydroxyprolines in the in vitro oxidative folding and biological activity of conotoxins.
2008,
Pubmed Loughnan,
Chemical and functional identification and characterization of novel sulfated alpha-conotoxins from the cone snail Conus anemone.
2004,
Pubmed
,
Xenbase Luzzati,
Physical structure of the excitable membrane of unmyelinated axons: X-ray scattering study and electrophysiological properties of pike olfactory nerve.
2000,
Pubmed McIntosh,
Conus peptides as probes for ion channels.
1999,
Pubmed Menin,
High throughput screening of bradykinin-potentiating peptides in Bothrops moojeni snake venom using precursor ion mass spectrometry.
2008,
Pubmed Miljanich,
Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.
2004,
Pubmed Mitchell,
Three-dimensional solution structure of conotoxin psi-PIIIE, an acetylcholine gated ion channel antagonist.
1998,
Pubmed Morris,
Stereochemical quality of protein structure coordinates.
1992,
Pubmed Nielsen,
Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels.
2002,
Pubmed Norton,
Mu-conotoxins as leads in the development of new analgesics.
2010,
Pubmed Olivera,
Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery.
2007,
Pubmed Ott,
Solution structure of mu-conotoxin GIIIA analysed by 2D-NMR and distance geometry calculations.
1991,
Pubmed Pardi,
Calibration of the angular dependence of the amide proton-C alpha proton coupling constants, 3JHN alpha, in a globular protein. Use of 3JHN alpha for identification of helical secondary structure.
1984,
Pubmed Quinton,
Fourier transform mass spectrometry: a powerful tool for toxin analysis.
2006,
Pubmed Rance,
Improved spectral resolution in cosy 1H NMR spectra of proteins via double quantum filtering.
1983,
Pubmed Safo,
Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA.
2000,
Pubmed
,
Xenbase Sandall,
A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo.
2003,
Pubmed Sato,
Active site of mu-conotoxin GIIIA, a peptide blocker of muscle sodium channels.
1991,
Pubmed Schirmeyer,
A subtle alternative splicing event of the Na(V)1.8 voltage-gated sodium channel is conserved in human, rat, and mouse.
2010,
Pubmed Schlumberger,
The marine polyether gambierol enhances muscle contraction and blocks a transient K(+) current in skeletal muscle cells.
2010,
Pubmed
,
Xenbase Schroeder,
Neuronally micro-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels.
2008,
Pubmed
,
Xenbase Shon,
A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom.
1997,
Pubmed Siemens,
Spider toxins activate the capsaicin receptor to produce inflammatory pain.
2006,
Pubmed Sokolov,
Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II.
2008,
Pubmed
,
Xenbase Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed Ueberheide,
Rapid sensitive analysis of cysteine rich peptide venom components.
2009,
Pubmed Vriend,
WHAT IF: a molecular modeling and drug design program.
1990,
Pubmed Wakamatsu,
Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations.
1992,
Pubmed West,
Mu-conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons.
2002,
Pubmed Wishart,
Relationship between nuclear magnetic resonance chemical shift and protein secondary structure.
1991,
Pubmed Yao,
Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA.
2008,
Pubmed
,
Xenbase Zhang,
Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels.
2006,
Pubmed Zhang,
Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels.
2007,
Pubmed
,
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