Abstract
Antitumor-analgesic peptide (AGAP) is a novel recombinant polypeptide. The primary study showed that AGAP 1.0 mg/kg exhibited strong analgesic and antitumor effects. The tail vein administration of AGAP potently reduced pain behaviors in mice induced by intraplantar injection of formalin or intraperitoneal injection of acetic acid, without affecting basal pain perception. To further assess the mechanisms of AGAP, the effects of AGAP on sodium channels were assessed using the whole-cell patch clamp recordings in dorsal root ganglia (DRG) neurons. The results showed that AGAP (3–1000 nM) inhibited the sodium currents in small-diameter DRG neurons in a dose-dependent manner. 1000 nM AGAP could inhibit the current density-voltage relationship curve of sodium channels in a voltage-dependent manner and negatively shift the activation curves. 1000 nM AGAP could reduce the tetrodotoxin-resistant (TTX-R) sodium currents by 42.8% in small-diameter DRG neurons. Further analysis revealed that AGAP potently inhibited NaV1.8 currents by 59.4%, and negatively shifted the activation and inactivation kinetics. 1000 nM AGAP also reduced the NaV1.9 currents by 33.7%, but had no significant effect on activation and inactivation kinetics. Thus, our results demonstrated that submicromolar concentrations of AGAP inhibited TTX-R sodium channel in rat small-diameter DRG neurons. It is concluded that these new results may better explain, at least in part, the analgesic properties of this polypeptide.
Highlights
Asian scorpion Buthus martensii Karsch, widely distributed in Mongolia, Korea, and China, has been one of the indispensable materials used in Chinese traditional medicine for thousands of years
Proteins from Scorpion venom modes of action fall within two major categories: one is pore-blocking proteins which block the movement of ions and the other alters the conformation of ion channel and the AGAP, Pain Relief through Sodium Channels statement of ion channel, such as open, closed or activation (Lai et al, 2004)
The primary study showed that AGAP exhibited strong analgesic and antitumor effects, but the analgesic mechanisms remain unclear in VGSCs (Liu et al, 2003)
Summary
Asian scorpion Buthus martensii Karsch, widely distributed in Mongolia, Korea, and China, has been one of the indispensable materials used in Chinese traditional medicine for thousands of years. It is well known that scorpion venom is complex mixture substances. It is a rich source interacting with various ion channels in excitable cell membranes. Scorpion polypeptides have long chain and short chain peptides. In 2003, the expression and purification of a novel antitumor-analgesic peptide (AGAP) were reported in E. coli (Herzog et al, 2001). BmK AGAP is a typical long-chain scorpion toxin, which is composed of 66 amino acids cross-linked by four disulfide bridges (Cys12–Cys, Cys16–Cys, Cys22–Cys, and Cys26-Cys). The gene cloning (GenBank No AF464898), protein expression, and characterization of the encoding gene of this peptide have been investigated (Liu et al, 2003). The primary study showed that AGAP exhibited strong analgesic and antitumor effects, but the analgesic mechanisms remain unclear in VGSCs (Liu et al, 2003)
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