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Toxins 2018, 10(2), 64; doi:10.3390/toxins10020064

Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain

1,2,†
,
3,†
,
1,2,†
,
1,2
,
3,4,* , 5,* and 1,2,*
1
The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
2
The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
3
Life Sciences College of Nanjing Agricultural University, 210095, Jiangsu, China
4
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China
5
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 27 December 2017 / Revised: 26 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
(This article belongs to the Special Issue Toxins and Ion Channels)
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Abstract

Jingzhaotoxin-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
Keywords: peptide toxin; sodium channels; Nav1.7; pain peptide toxin; sodium channels; Nav1.7; pain
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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.

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