Synergetic Action of Domain II and IV Underlies Persistent Current Generation in Nav1.3 as revealed by a tarantula toxin

Abstract

The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3.

Mutations in SCN3A cause early infantile epileptic encephalopathy

“…This toxin increases Nav1.3-mediated I NaP via interaction with DII and DIV. 55 Interestingly, focal application of RTX-VII to the surface of the cerebral cortex of adult rats induced seizures, consistent with a potentially ictogenic effect of increased Nav1.3 I NaP and supporting the pathogenic mechanism proposed here. Why the p.Pro1333Leu mutation, located in DIII, also increased I NaP , remains unclear.…”

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

“…These results indicated that JZTX-I was not selective for hNav1.5, but instead interacts with several VGSC subtypes. This is in contrast to JZTX-II and JZTX-III (Rong et al, 2011;Tao et al, 2013a), another peptide toxins isolated from the same venom of Chilobrachys jingzhao, which are selective for hNav1.5. Given that JZTX-I and JZTX-II are similar in function but differ in isoform selectivity, a comparison of these two toxins should improve our understanding of the structural characteristics that determine toxin selectivity.…”

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

“…Data were analyzed by softwares igo pro 6.10A, Excel 2010 and sigmaplot 10.0. Whole‐cell patch‐clamp recordings were performed as previously described .…”