Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na V1.8 and has a long-lasting analgesic activity

Grzegorz Bulaj; Min Min Zhang; Brad R. Green; Brian Fiedler; Richard T. Layer; Sue Wei; Jacob S. Nielsen; Scott J. Low; Brian D. Klein; John D. Wagstaff; Linda Chicoine; T. Patrick Harty; Heinrich Terlau; Doju Yoshikami; Baldomero M. Olivera

doi:10.1021/bi060159+

Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na _V1.8 and has a long-lasting analgesic activity

Grzegorz Bulaj^*, Min Min Zhang, Brad R. Green, Brian Fiedler, Richard T. Layer, Sue Wei, Jacob S. Nielsen, Scott J. Low, Brian D. Klein, John D. Wagstaff, Linda Chicoine, T. Patrick Harty, Heinrich Terlau, Doju Yoshikami, Baldomero M. Olivera

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

77 Zitate (Scopus)

Abstract

μO-Conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat Na_V1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.

Originalsprache	Englisch
Zeitschrift	Biochemistry
Jahrgang	45
Ausgabenummer	23
Seiten (von - bis)	7404-7414
Seitenumfang	11
ISSN	0006-2960
DOIs	https://doi.org/10.1021/bi060159+
Publikationsstatus	Veröffentlicht - 13.06.2006

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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10.1021/bi060159+

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Bulaj, G., Zhang, M. M., Green, B. R., Fiedler, B., Layer, R. T., Wei, S., Nielsen, J. S., Low, S. J., Klein, B. D., Wagstaff, J. D., Chicoine, L., Harty, T. P., Terlau, H., Yoshikami, D., & Olivera, B. M. (2006). Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na _V1.8 and has a long-lasting analgesic activity. Biochemistry, 45(23), 7404-7414. https://doi.org/10.1021/bi060159+

@article{955a01a7aa8945a9bfe72cc6f703fbe7,

title = "Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na V1.8 and has a long-lasting analgesic activity",

abstract = "μO-Conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat NaV1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.",

author = "Grzegorz Bulaj and Zhang, {Min Min} and Green, {Brad R.} and Brian Fiedler and Layer, {Richard T.} and Sue Wei and Nielsen, {Jacob S.} and Low, {Scott J.} and Klein, {Brian D.} and Wagstaff, {John D.} and Linda Chicoine and Harty, {T. Patrick} and Heinrich Terlau and Doju Yoshikami and Olivera, {Baldomero M.}",

year = "2006",

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day = "13",

doi = "10.1021/bi060159+",

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volume = "45",

pages = "7404--7414",

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Bulaj, G, Zhang, MM, Green, BR, Fiedler, B, Layer, RT, Wei, S, Nielsen, JS, Low, SJ, Klein, BD, Wagstaff, JD, Chicoine, L, Harty, TP, Terlau, H, Yoshikami, D & Olivera, BM 2006, 'Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na _V1.8 and has a long-lasting analgesic activity', Biochemistry, Jg. 45, Nr. 23, S. 7404-7414. https://doi.org/10.1021/bi060159+

TY - JOUR

T1 - Synthetic μO-conotoxin MrVIB blocks TTX-resistant sodium channel Na V1.8 and has a long-lasting analgesic activity

AU - Bulaj, Grzegorz

AU - Zhang, Min Min

AU - Green, Brad R.

AU - Fiedler, Brian

AU - Layer, Richard T.

AU - Wei, Sue

AU - Nielsen, Jacob S.

AU - Low, Scott J.

AU - Klein, Brian D.

AU - Wagstaff, John D.

AU - Chicoine, Linda

AU - Harty, T. Patrick

AU - Terlau, Heinrich

AU - Yoshikami, Doju

AU - Olivera, Baldomero M.

PY - 2006/6/13

Y1 - 2006/6/13

N2 - μO-Conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat NaV1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.

AB - μO-Conotoxin MrVIB is a blocker of voltage-gated sodium channels, including TTX-sensitive and -resistant subtypes. A comprehensive characterization of this peptide has been hampered by the lack of sufficient synthetic material. Here, we describe the successful chemical synthesis and oxidative folding of MrVIB that has made an investigation of the pharmacological properties and therapeutic potential of the peptide feasible. We show for the first time that synthetic MrVIB blocks rat NaV1.8 sodium channels and has potent and long-lasting local anesthetic effects when tested in two pain assays in rats. Furthermore, MrVIB can block propagation of action potentials in A- and C-fibers in sciatic nerve as well as skeletal muscle in isolated preparations from rat. Our work provides the first example of analgesia produced by a conotoxin that blocks sodium channels. The emerging diversity of antinociceptive mechanisms targeted by different classes of conotoxins is discussed.

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