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

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/kappa-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 +/- 0.211M) of Na(v)1.5 expressed in Chinese hamster ovary (CHO-K1 cells. JZTX-XI significantly shifted the activation to more depolarized voltages and decreased the deactivation of Na(v)1.5 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 (alpha-scorpion toxins) with site 4 toxins (beta-scorpion and spider toxins) by targeting multiple sites on Na(v)1.5. The unique properties displayed by JZTX-XI in its inhibitory activity on Na(v)1.5 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 Na(v)1.5 and toxin-channel interactions. (C) 2014 Elsevier Ltd. All rights reserved.