title: The tarantula toxin jingzhaotoxin-XI (κ-theraphotoxin-Cj1a) regulates the activation and inactivation of the voltage-gated sodium channel Nav1.5.
abstract: Specific peptide toxins interact with voltage-gated sodium channels by regulating the activation or inactivation of targeted channels. However, few toxins possessing dual effects have been identified. In the present study, we showed that jingzhaotoxin-XI/κ-theraphotoxin-Cj1a (JZTX-XI), a 34-residue peptide from the venom of the Chinese spider Chilobrachys jingzhao, inhibits the sodium conductance (IC50 = 124 ± 26 nM) and slows the fast inactivation (EC50 = 1.18 ± 0.2 μM) of Nav1.5 expressed in Chinese hamster ovary (CHO-K1) cells. JZTX-XI significantly shifted the activation to more depolarized voltages and decreased the deactivation of Nav1.5 currents upon extreme depolarization, but only slightly affected voltage-dependence of steady-state inactivation. In addition, JZTX-XI caused an approximately five-fold decrease in the rate of recovery from inactivation and an approximately 1.9-fold reduction in the closed-state inactivation rate. Our data suggest that JZTX-XI integrates the functions of site 3 toxins (α-scorpion toxins) with site 4 toxins (β-scorpion and spider toxins) by targeting multiple sites on Nav1.5. The unique properties displayed by JZTX-XI in its inhibitory activity on Nav1.5 suggest that its mechanism of action is distinct from those of site 3 and site 4 toxins, making JZTX-XI a useful probe for investigating the gating mechanism of Nav1.5 and toxin-channel interactions.
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Tang
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Yunxiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Zhaotun
authors.initials: Z
authors.lastname: Hu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Meichi
authors.initials: M
authors.lastname: Wang
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China. Electronic address: liuzh@hunnu.edu.cn.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha 410081, China. Electronic address: liangsp@hunnu.edu.cn.
authors.forename: Songping
authors.initials: S
authors.lastname: Liang
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000633:toxicity*; D013111:Spider Venoms / Q000633:toxicity*; D061567:Voltage-Gated Sodium Channel Blockers / Q000633:toxicity*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D010455:Peptides; D013111:Spider Venoms; D061567:Voltage-Gated Sodium Channel Blockers; C525630:jingzhaotoxin XI, Chilobrachys jingzhao
keywords: Activation; Gating mechanism; Inactivation; Jingzhaotoxin-XI; Na(v)1.5