| Registro completo |
| Provedor de dados: |
ArchiMer
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| País: |
France
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| Título: |
A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors
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| Autores: |
Favreau, Philippe
Benoit, Evelyne
Hocking, Henry G.
Carlier, Ludovic
D'Hoedt, Dieter
Leipold, Enrico
Markgraf, Rene
Schlumberger, Sebastien
Cordova, Marco A.
Gaertner, Hubert
Paolini-bertrand, Marianne
Hartley, Oliver
Tytgat, Jan
Heinemann, Stefan H.
Bertrand, Daniel
Boelens, Rolf
Stoecklin, Reto
Molgo, Jordi
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| Data: |
2012-07
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| Ano: |
2012
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| Palavras-chave: |
Cone snail venom
Mu-conotoxin
Voltage-gated sodium channel
Nicotinic acetylcholine receptor
Myorelaxant
Twitch tension
NMR structure
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| Resumo: |
BACKGROUND AND PURPOSE The mu-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 mu-conopeptide (mu-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH mu-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. mu-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. KEY RESULTS Synthetic mu-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC50= 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with mu-SIIIA, mu-SmIIIA and mu-PIIIA. mu-CnIIIC blocked NaV1.4 (IC50= 1.3 nM) and NaV1.2 channels in a long-lasting manner. Cardiac NaV1.5 and DRG-specific NaV1.8 channels were not blocked at 1 mu M. mu-CnIIIC also blocked the a3 beta 2 nAChR subtype (IC50= 450 nM) and, to a lesser extent, on the a7 and a4 beta 2 subtypes. Structure determination of mu-CnIIIC revealed some similarities to a-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS mu-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.
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| Tipo: |
Text
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| Idioma: |
Inglês
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| Identificador: |
https://archimer.ifremer.fr/doc/00467/57830/60132.pdf
https://archimer.ifremer.fr/doc/00467/57830/60133.pdf
https://archimer.ifremer.fr/doc/00467/57830/60134.pdf
DOI:10.1111/j.1476-5381.2012.01837.x
https://archimer.ifremer.fr/doc/00467/57830/
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| Editor: |
Wiley-blackwell
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| Formato: |
application/pdf
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| Fonte: |
British Journal Of Pharmacology (0007-1188) (Wiley-blackwell), 2012-07 , Vol. 166 , N. 5 , P. 1654-1668
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| Direitos: |
info:eu-repo/semantics/openAccess
restricted use
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