Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain
AbstractJingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold. The reverse mutant R800D at the corresponding position in Nav1.5 greatly increased its binding affinity to JZTX-34. This implies that JZTX-34 binds to DIIS3-S4 linker of Nav1.7 and the critical residue of Nav1.7 is D816. Unlike β-scorpion toxin trapping sodium channel in an open state, activity of JZTX-34 requires the sodium channel to be in a resting state. JZTX-34 exhibits an obvious analgesic effect in a rodent pain model. Especially, it shows a longer duration and is more effective than morphine in hot pain models. In a formalin-induced pain model, JZTX-34 at dose of 2 mg/kg is equipotent with morphine (5 mg/kg) in the first phase and several-fold more effective than morphine in second phase. Taken together, our data indicate that JZTX-34 releases pain by selectively binding to the domain II voltage sensor of Nav1.7 in a closed configuration. View Full-Text
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Zeng, X.; Li, P.; Chen, B.; Huang, J.; Lai, R.; Liu, J.; Rong, M. Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain. Toxins 2018, 10, 64.
Zeng X, Li P, Chen B, Huang J, Lai R, Liu J, Rong M. Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain. Toxins. 2018; 10(2):64.Chicago/Turabian Style
Zeng, Xiongzhi; Li, Pengpeng; Chen, Bo; Huang, Juan; Lai, Ren; Liu, Jingze; Rong, Mingqiang. 2018. "Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain." Toxins 10, no. 2: 64.
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