μ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects  

作　　者：Yun-xiao Zhang De-zheng Peng Qing-feng Zhang Biao Huang Qiu-chu Yang Dong-fang Tang Min-zhi Chen Ming-qiang Rong Zhong-hua Liu 

机构地区：[1]The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China

出　　处：《Acta Pharmacologica Sinica》2019年第7期859-866,共8页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China (81573320 and 31670783).

摘　　要：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 identi?ed 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 Nav1.7 (IC50 378 nM), followed by Nav1.6 (IC50 547 nM), Nav1.2 (IC50 728 nM), Nav1.3 (IC50 2.2 μM) and Nav1.4 (IC50 3.2 μM), and produced negligible inhibitory effect on Nav1.5, Nav1.8, and Nav1.9, even at high concentrations of up to 10 μM. Furthermore, this peptide did not signi?cantly affect the activation and inactivation of Nav1.7. Using site-directed mutagenesis of Nav1.7 and Nav1.4, 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.

关 键 词：μ-TRTX-Ca1a TARANTULA SPIDER PEPTIDE hNav1.7 ELECTROPHYSIOLOGY ANALGESIC activity 

分 类 号：R512.910.2[医药卫生—内科学]