The Functional Property Changes of Muscular Na(v)1.4 and Cardiac Na(v)1.5 Induced by Scorpion Toxin BmK AGP-SYPU1 Mutants Y42F and Y5F.
Scorpion toxins are invaluable therapeutic leads and pharmacological tools which influence the voltage-gated sodium channels. However, the details were still unclear about the structure-function relationship of scorpion toxins on VGSC subtypes. In the previous study, we reported one α-type scorpion toxin Bmk AGP-SYPU1 and its two mutants (Y5F and Y42F) which had been demonstrated to ease pain in mice acetic acid writhing test. However, the function of Bmk AGP-SYPU1 on VGSCs is still unknown. In this study, we examined the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNa(v)1.4 and hNa(v)1.5 heterologously expressed CHO cell lines by using Na⁺-specialized fluorescent dye and whole-cell patch clamp. The data showed that BmK AGP-SYPU1 displayed as an activator of hNa(v)1.4 and hNa(v)1.5, which might indeed contribute to its biotoxicity to muscular and cardiac system and exhibited the functional properties of both the α-type and β-type scorpion toxin. Notably, Y5F mutant exhibited lower activatory effects on hNa(v)1.4 and hNa(v)1.5 compared with BmK AGP-SYPU1. Y42F was an enhanced activator and confirmed that the conserved Tyr42 was the key amino acid involved in bioactivity or biotoxicity. These data provided a deep insight into the structure-function relationship of BmK AGP-SYPU1, which may be the guidance for engineering α-toxin with high selectivity on VGSC subtypes.
Xiangxue
X
Meng
Yijia
Y
Xu
Mingyi
M
Zhao
Fangyang
F
Wang
Yuanyuan
Y
Ma
Yao
Y
Jin
Yanfeng
Y
Liu
Yongbo
Y
Song
Jinghai
J
Zhang
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D003412:Cricetulus; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017433:Protein Structure, Secondary; D012604:Scorpion Venoms / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship
D062553:NAV1.4 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D012604:Scorpion Venoms; D012964:Sodium