Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain
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 corresp...
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MDPI AG
2018-02-01
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| Series: | Toxins |
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| Online Access: | http://www.mdpi.com/2072-6651/10/2/64 |
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| author | Xiongzhi Zeng Pengpeng Li Bo Chen Juan Huang Ren Lai Jingze Liu Mingqiang Rong |
| author_facet | Xiongzhi Zeng Pengpeng Li Bo Chen Juan Huang Ren Lai Jingze Liu Mingqiang Rong |
| author_sort | Xiongzhi Zeng |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-04-14T00:27:37Z |
| publishDate | 2018-02-01 |
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| series | Toxins |
| spelling | doaj.art-96fedad530e54ebfbd916caa68b26f2e2022-12-22T02:22:39ZengMDPI AGToxins2072-66512018-02-011026410.3390/toxins10020064toxins10020064Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against PainXiongzhi Zeng0Pengpeng Li1Bo Chen2Juan Huang3Ren Lai4Jingze Liu5Mingqiang Rong6The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, ChinaLife Sciences College of Nanjing Agricultural University, 210095, Jiangsu, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, ChinaLife Sciences College of Nanjing Agricultural University, 210095, Jiangsu, ChinaKey Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, ChinaJingzhaotoxin-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.http://www.mdpi.com/2072-6651/10/2/64peptide toxinsodium channelsNav1.7pain |
| spellingShingle | Xiongzhi Zeng Pengpeng Li Bo Chen Juan Huang Ren Lai Jingze Liu Mingqiang Rong Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain Toxins peptide toxin sodium channels Nav1.7 pain |
| title | Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain |
| title_full | Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain |
| title_fullStr | Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain |
| title_full_unstemmed | Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain |
| title_short | Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain |
| title_sort | selective closed state nav1 7 blocker jztx 34 exhibits analgesic effects against pain |
| topic | peptide toxin sodium channels Nav1.7 pain |
| url | http://www.mdpi.com/2072-6651/10/2/64 |
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