Bulaj Grzegorz, Zhang Min-Min, Green Brad R, Fiedler Brian, Layer Richard T, Wei Sue, Nielsen Jacob S, Low Scott J, Klein Brian D, Wagstaff John D, Chicoine Linda, Harty T Patrick, Terlau Heinrich, Yoshikami Doju, Olivera Baldomero M
Department of Biology, The University of Utah, Salt Lake City, Utah 84112, USA.
Biochemistry. 2006 Jun 13;45(23):7404-14. doi: 10.1021/bi060159+.
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.
μ-芋螺毒素MrVIB是电压门控钠通道的阻滞剂，包括对河豚毒素敏感和耐药的亚型。由于缺乏足够的合成材料，对这种肽的全面表征受到了阻碍。在此，我们描述了MrVIB的成功化学合成和氧化折叠，这使得对该肽的药理特性和治疗潜力进行研究成为可能。我们首次表明，合成的MrVIB可阻断大鼠NaV1.8钠通道，并且在大鼠的两种疼痛试验中测试时具有强效且持久的局部麻醉作用。此外，MrVIB可阻断坐骨神经A纤维和C纤维以及大鼠离体标本中骨骼肌的动作电位传播。我们的工作提供了由一种阻断钠通道的芋螺毒素产生镇痛作用的首个实例。讨论了不同类别的芋螺毒素所靶向的抗伤害感受机制的新出现的多样性。
