Data/hora: 10/06/2024 07:55:47

Provedor de dados: | Institutional Archive of Ifreme (ArchiMer)
País: | France
Título: | A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors
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.
Data: | 2012-07
Ano: | 2012
Palavras-chave: | Cone snail venom; Mu-conotoxin; Voltage-gated sodium channel; Nicotinic acetylcholine receptor; Myorelaxant; Twitch tension; NMR structure.
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.
Tipo: | Text
Idioma: | Inglês

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/

Editor: | Wiley-blackwell
Formato: | application/pdf
Fonte: | British Journal Of Pharmacology (0007-1188) (Wiley-blackwell), 2012-07 , Vol. 166 , N. 5 , P. 1654-1668

Fonte:

info:eu-repo/semantics/openAccess

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