Introduction
Jingzhaotoxin-III (β-TRTX-Cj1α) is a kind of sodium channel gating modifier which is from the tarantula Chilobrachys jingzhao. It can selectively inhibit the activation of cardiac sodium channel but not the neuronal subtypes.
Pharmacologic action
Similar to the hanatoxin1 and SGTx1, Jingzhaotoxin-III inhibits NaV channels of rat cardiac myocytes by modifying voltage-dependent gating and binding to Kv2.1 channel (Kd = 0.43 μM) with an action model. Like atracotoxins, magi5 and ProTx-II, Jingzhaotoxin-III adopts a Janus-faced surface profile, in which a large hydrophobic patch is formed on the surface. However, the 5 positively charged and 2 negatively charged residues are arranged on the opposite surface or on the edge of the hydrophobic patch. Using a site-directed Ala scanning method, all charged and hydrophobic residues were mutated to investigate which surface is more important for Jingzhaotoxin-III binding to the sodium channel. The results showed that mutations of these residues did not evidently change the secondary structure of Jingzhaotoxin-III. It is reported that some site 4 toxins have the ability to bind to liposomes, which may raise their affinity for Nav1.5. Therefore, the hydrophobic patch is supposed to be primarily important for facilitating entry into the phospholipid bilayer. It was speculated that Jingzhaotoxin-III might adopt the mechanism for binding to NaV 1.5, similar to ProTx-II.
Function
The experiment suggested that Jingzhaotoxin-III specifically inhibited NaV channels of rat cardiac myocytes with an IC50 of 0.38 μM and followed by shifting activated voltage in a depolarizing direction. Besides, Jingzhaotoxin-III is ineffective on CaV and NaV channels of rat DRG cells. Furthermore, Jingzhaotoxin-III is specific for Tetrodotoxin-resistant (TTX-resistant) cardiac sodium channels and did not affect voltage-gated sodium channels in dorsal root ganglion neurons. And research showed that Jingzhaotoxin-III selectively inhibited the activation of Nav1.5, the isoform predominantly expressed in cardiac myocytes. However, Jingzhaotoxin-III did not inhibit the activation of not Nav1.7, the isoform predominantly expressed in peripheral sensory neurons.
Pharmacokinetics and metabolism
Jingzhaotoxin-III modulates the activity of sodium channels through a mechanism distinct from that of classic scorpion β toxins because the toxin positively shifted Nav1.5 activation by 13 mV. Jingzhaotoxin-III can speed up the deactivation kinetics, from τ = 37 ± 2.5ms (n = 5) in control to τ = 13.8 ± 0.9 ms (n = 5) in present of the toxin, as the scaled records for depolarization to +100 mV in the presence of 5 μM toxin showed. The results indicate that the currents elicited by strong depolarization in presence of toxin are attributed to the opening of toxin-bound channels.
References:
1. Xiao, Y., Tang, J., Yang, Y., Wang, M., Hu, W., Xie, J., ... & Liang, S. (2004). Jingzhaotoxin-III, a novel spider toxin inhibiting activation of voltage-gated sodium channel in rat cardiac myocytes. Journal of Biological Chemistry.
2. Rong, M., Chen, J., Tao, H., Wu, Y., Jiang, P., Lu, M., ... & Zeng, X. (2011). Molecular basis of the tarantula toxin jingzhaotoxin-III (β-TRTX-Cj1α) interacting with voltage sensors in sodium channel subtype Nav1. 5. The FASEB Journal, 25(9), 3177-3185.
3. Liao, Z., Yuan, C., Peng, K., Xiao, Y., & Liang, S. (2007). Solution structure of Jingzhaotoxin-III, a peptide toxin inhibiting both Nav1. 5 and Kv2. 1 channels. Toxicon, 50(1), 135-143.
