2yen
From Proteopedia
Solution structure of the skeletal muscle and neuronal voltage gated sodium channel antagonist mu-conotoxin CnIIIC
Structural highlights
FunctionGM3C_CONCN Mu-conotoxins block voltage-gated sodium channels (Nav). This synthetic toxin blocks both voltage-gated sodium channels and nicotinic acetylcholine receptor (nAChR). Inhibits the skeletal muscle rNav1.4/SCN4A (IC(50)=1.3 nM) and the brain rNav1.2/SCN2A in a long-lasting manner. A low inhibition is also observed on neuronal mNav1.6/SCN8A and mNav1.7/SCN9A. Modestly blocks nAChR alpha-3/beta-2 subtype (IC(50)=450 nM) (partially reversible) and, to a lesser extent, alpha-7 and alpha-4/beta-2 subtypes (reversible). In vitro, decreases twitch tension in mouse hemidiaphragms (IC(50)=150 nM), and displays a high blocking effect in mouse extensor digitorum longus muscles (IC(50)=46 nM).[1] Publication Abstract from PubMedBACKGROUND AND PURPOSE The micro-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 performed a pharmacological characterisation of a new micro-conopeptide (mu-CnIIIC) on multiple preparations and molecular targets to gauge its potential as a myorelaxant. EXPERIMENTAL APPROACH The micro-CnIIIC was sequenced, synthesized, and characterized by its ability to block directly-elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. micro-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs. Pharmacological investigations were extended to voltage-gated potassium channels and nAChRs to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS Synthetic mu-CnIIIC potently 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), as compared to micro-SIIIA, micro-SmIIIA and micro-PIIIA. mu-CnIIIC blocked Na(V) 1.4 (IC(50) = 1.3 nM) and Na(V) 1.2 in a long-lasting manner. Cardiac Na(V) 1.5 and DRG-specific Na(V) 1.8 were not blocked at 1 muM. An activity was unveiled on the alpha3beta2 nAChR subtype (IC(50) = 450 nM) and, to a lesser extent, on the alpha7 and alpha4beta2 subtypes. Structure determination of micro-CnIIIC revealed some similarities to alpha-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS mu-CnIIIC potently blocks VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its new atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels. Pharmacological characterization of a novel mu-conopeptide, CnIIIC, indicates potent and preferential inhibition of sodium channel subtypes (Na(V) 1.2/1.4) and reveals unusual activity on neuronal nicotinic acetylcholine receptors.,Favreau P, Benoit E, Hocking HG, Carlier L, D'hoedt D, Leipold E, Markgraf R, Schlumberger S, Cordova MA, Gaertner H, Paolini-Bertrand M, Hartley O, Tytgat J, Heinemann SH, Bertrand D, Boelens R, Stocklin R, Molgo J Br J Pharmacol. 2012 Jan 9. doi: 10.1111/j.1476-5381.2012.01837.x. PMID:22229737[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Conus consors | Large Structures | Benoit E | Bertrand D | Boelens R | Carlier L | Cordova MA | D'hoedt D | Favreau P | Gaertner H | Hartley O | Heinemann SH | Hocking HG | Leipold E | Markgraf R | Molgo J | Paolini-Bertrand M | Schlumberger S | Stocklin R | Tytgat J
