TY - JOUR AU - Zhang Yun-xiao AU - Peng De-zheng AU - Zhang Qing-feng AU - Huang Biao AU - Yang Qiu-chu AU - Tang Dong-fang AU - Chen Min-zhi AU - Rong Ming-qiang AU - Liu Zhong-hua PY - 2019 TI - µ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects JF - Acta Pharmacologica Sinica; Vol 40, No 7 (July 2019): Acta Pharmacologica Sinica Y2 - 2019 KW - N2 - Human genetic and pharmacological studies have demonstrated that voltage-gated sodium channels (VGSCs) are promising therapeutic targets for the treatment of pain. Spider venom contains many toxins that modulate the activity of VGSCs. To date, only 0.01% of such spider toxins has been explored, and thus there is a great potential for discovery of novel VGSC modulators as useful pharmacological tools or potential therapeutics. In the current study, we identified a novel peptide, µ-TRTX-Ca1a (Ca1a), in the venom of the tarantula Cyriopagopus albostriatus . This peptide consisted of 38 residues, including 6 cysteines, i.e. IFECSISCEIEKEGNGKKCKPKKCKGGWKCKFNICVKV. In HEK293T or ND7/23 cells expressing mammalian VGSCs, this peptide exhibited the strongest inhibitory activity on Na v 1.7 (IC 50 378 nM), followed by Na v 1.6 (IC 50 547 nM), Na v 1.2 (IC 50 728 nM), Na v 1.3 (IC 50 2.2 µM) and Na v 1.4 (IC 50 3.2 µM), and produced negligible inhibitory effect on Na v 1.5, Na v 1.8, and Na v 1.9, even at high concentrations of up to 10 µM. Furthermore, this peptide did not significantly affect the activation and inactivation of Na v 1.7. Using site-directed mutagenesis of Na v 1.7 and Na v 1.4, we revealed that its binding site was localized to the DIIS3-S4 linker region involving the D816 and E818 residues. In three different mouse models of pain, pretreatment with Cala (100, 200, 500 µg/kg) dose-dependently suppressed the nociceptive responses induced by formalin, acetic acid or heat. These results suggest that Ca1a is a novel neurotoxin against VGSCs and has a potential to be developed as a novel analgesic. UR - http://www.chinaphar.com/article/view/9989