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

Molecular determinant for the tarantula toxin Jingzhaotoxin-I slowing the fast inactivation of voltage-gated sodium channels

“…These differences were not significant except that a little positive shift was observed in the activation curve of hNav1.5. The effect of JZTX-I on the activation of VGSC subtypes was opposite to that of JZTX-II and RTX-VII , which caused a hyperpolarized shift of VGSC activation and JZTX-XI (Tang et al, 2014), which changed the voltage dependence of activation for Nav1.5 with an approximately 40 mV shift of the half-maximal activation voltage in the depolarizing direction. However, it was similar to that of CvIV4 (Rowe et al, 2011), which did not significantly shift the voltage-dependence of activation, suggesting that 1 mM JZTX-I had no obvious effect on the activation kinetic.…”

“…The voltage dependence of steady-state inactivation is another important property of VGSCs that can modulate the excitability of neurons (Herzog et al, 2003) and be modified by toxins from spider (Tang et al, 2014) and scorpion (Zhu et al, 2009). In order to determine whether JZTX-I could alter the voltage dependence of steady-state inactivation, we also tested the effect of 1 mM JZTX-I on steady-state inactivation of four VGSC subtypes (rNav1.2, rNav1.3, hNav1.5, and hNav1.7) using a standard two-pulse protocol.…”

The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity

“…( c) Activity of pure, native Pre1a on rNa V 1.3 and hNa V 1.7 exressed in Xenopus oocytes demonstrating inhibition of inactivation and peak current, respectively. ( d) Sequence alignment of TRTX-Pre1a with Na V modulating Theraphotoxins 13, 20, 22, 41, 47–50, 55, 65–68 . Percent similarity was calculated comparing the number of identical (dark gray) and similar (light gray) amino acids. …”

“…Although several spider venom peptides (such as JzTxI and JzTxII) have previously been shown to preferentially inhibit Na V channel fast inactivation, they are either relatively non-selective 48 or preferentially target Na V 1.5 49, 50 . Two other spider peptides (ProTx-II and JzTxIV) have been found to inhibit both peak current and fast inactivation of Na V channels 20, 25 , much like Pre1a.…”

Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways

“…Broadly, they either (i) prevent channel opening in response to membrane depolarization by trapping the VSD II in the closed state; (ii) facilitate channel opening by trapping VSD II in open state or (iii) prevent channel inactivation by binding DIV S4 in the closed state to impair the movement of the inactivation gate [15,18,63]. Curiously, an integrated pharmacology of Site 3 and Site 4 indicates multiple binding site interactions by the same toxin [91,92]. For example, the toxic fraction PhTx2 from the venom of P. nigriventer not only prolonged the inactivation and deactivation (Site 3 phenotype) of the Na V channel but also shifted the voltage dependence of activation (Site 4 phenotype) and steady-state inactivation towards negative potentials (Site 3 phenotype) [89].…”