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

Toxicon. 2014 Dec 15:92:6-13. doi: 10.1016/j.toxicon.2014.09.002. Epub 2014 Sep 18.

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.

Keywords: Activation; Gating mechanism; Inactivation; Jingzhaotoxin-XI; Na(v)1.5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Inhibitory Concentration 50
  • Ion Channel Gating / drug effects*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism*
  • Patch-Clamp Techniques
  • Peptides / toxicity*
  • Spider Venoms / toxicity*
  • Voltage-Gated Sodium Channel Blockers / toxicity*

Substances

  • NAV1.5 Voltage-Gated Sodium Channel
  • Peptides
  • Spider Venoms
  • Voltage-Gated Sodium Channel Blockers
  • jingzhaotoxin XI, Chilobrachys jingzhao