Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity.
MuO-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.
Bulaj
Grzegorz
G
Department of Biology, The University of Utah, Salt Lake City, Utah 84112, USA. bulaj@biology.utah.edu
Zhang
Min-Min
MM
Green
Brad R
BR
Fiedler
Brian
B
Layer
Richard T
RT
Wei
Sue
S
Nielsen
Jacob S
JS
Low
Scott J
SJ
Klein
Brian D
BD
Wagstaff
John D
JD
Chicoine
Linda
L
Harty
T Patrick
TP
Terlau
Heinrich
H
Yoshikami
Doju
D
Olivera
Baldomero M
BM
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels; D013779:Tetrodotoxin / Q000494:pharmacology*
D000700:Analgesics; D020916:Conotoxins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568319:Scn10a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin