The tarantula toxin jingzhaotoxin-XI (κ-theraphotoxin-Cj1a) regulates the activation and inactivation of the voltage-gated sodium channel Nav1.5

• Published in: Toxicon (Oxford) 2014-12, Vol.92, p.6-13
• Main Authors: Tang, Cheng, Zhou, Xi, Huang, Yin, Zhang, Yunxiao, Hu, Zhaotun, Wang, Meichi, Chen, Ping, Liu, Zhonghua, Liang, Songping
• Format: Article
• Language: English
• Subjects: Activation; Animals; Araneae; Channels; CHO Cells; Cricetinae; Cricetulus; Depolarization; Gating mechanism; Inactivation; Inhibitory Concentration 50; Ion Channel Gating - drug effects; Jingzhaotoxin-XI; Nav1.5; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Patch-Clamp Techniques; Peptides; Peptides - toxicity; Sodium; Spider Venoms - toxicity; Spiders; Toxins; Voltage-Gated Sodium Channel Blockers - toxicity
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2014.09.002

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. •JZTX-XI inhibits the sodium conductance and slows the fast inactivation.•Its mechanism of action is distinct from those of site 3 and site 4 toxins.•It is useful for investigating Nav1.5 gating mechanism and toxin-channel interactions.