title: A Novel Toxin from Haplopelma lividum Selectively Inhibits the NaV1.8 Channel and Possesses Potent Analgesic Efficacy.
abstract: Spider venoms are a complex mixture of peptides with a large number of neurotoxins targeting ion channels. Although thousands of peptide toxins have been identified from venoms of numerous species of spiders, many unknown species urgently need to be investigated. In this study, a novel sodium channel inhibitor, µ-TRTX-Hl1a, was identified from the venom ofHaplopelma lividum. It contained eight cysteines and formed a conserved cysteine pattern of ICK motif. µ-TRTX-Hl1a inhibited the TTX-resistant (TTX-r) sodium channel current rather than the TTX-sensitive (TTX-s) sodium channel current. Meanwhile, µ-TRTX-Hl1a selectively inhibited NaV1.8 with an IC50value of 2.19 μM. Intraperitoneal injection of µ-TRTX-Hl1a dose-dependently reduced inflammatory and neuropathic pain in rodent models of formalin-induced paw licking, tail-flicking, acetic acid-induced writhing, and hot plate test. It showed a better analgesic effect than morphine in inflammatory pain and equipotent effect to morphine in neuropathic pain. These findings demonstrate that µ-TRTX-Hl1a might be a valuable tool for physiology studies on NaV1.8 and a promising lead molecule for pain therapeutics.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China. mengping@mail.kiz.ac.cn.|United Laboratory of Natural Peptide of University of Science and Technology of China & Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan, China. mengping@mail.kiz.ac.cn.|Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China. mengping@mail.kiz.ac.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Meng
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 6550 1000, Denmark. hhuang@bmb.sdu.dk.|The Danish Diabetes Academy, Odense 6550 1000, Denmark. hhuang@bmb.sdu.dk.
authors.forename: Honggang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Life Sciences College, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China. wang.gan@outlook.com.
authors.forename: Gan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China. yslzoology@163.com.|United Laboratory of Natural Peptide of University of Science and Technology of China & Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan, China. yslzoology@163.com.|Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China. yslzoology@163.com.
authors.forename: Shilong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China. lvqm@mail.kiz.ac.cn.|United Laboratory of Natural Peptide of University of Science and Technology of China & Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan, China. lvqm@mail.kiz.ac.cn.|Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China. lvqm@mail.kiz.ac.cn.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei, China. jzliu21@heinfo.net.
authors.forename: Jingze
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China. rlai@mail.kiz.ac.cn.|United Laboratory of Natural Peptide of University of Science and Technology of China & Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan, China. rlai@mail.kiz.ac.cn.|Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China. rlai@mail.kiz.ac.cn.
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China. rongmingqiang@mail.kiz.ac.cn.|United Laboratory of Natural Peptide of University of Science and Technology of China & Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan, China. rongmingqiang@mail.kiz.ac.cn.|Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China. rongmingqiang@mail.kiz.ac.cn.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Rong
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy; D017422:Sequence Analysis, DNA; D013111:Spider Venoms / Q000737:chemistry / Q000494:pharmacology*; D013112:Spiders; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D062559:NAV1.8 Voltage-Gated Sodium Channel; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers; D009020:Morphine
keywords: NaV1.8; analgesia; neurotoxin; spider; venom