Steric hindrance from loop length, not the specific residues, defines BmK I action. DIV/S3-S4 Loop Length Determines Nav1.8 Insensitivity to the Scorpion α-Like Toxin BmK I.

Authors

Lu Zhao, Xinghua Feng, Lele Tang, Lu Tao, Zhiyong Tan, Jiajun Wang, Yonghua Ji

Published in

Toxicon : official journal of the International Society on Toxinology. Pages 109345. Oct 30, 2026. Epub Oct 30, 2026.

Abstract

Nav1.8, a voltage-gated sodium channel predominantly expressed in dorsal root ganglion neurons, is a key mediator of pain signaling and an established therapeutic target. However, its direct interaction with BmK I, an α-like scorpion toxin considered to be the primary factor in scorpion sting pain, has remained uncertain. By whole-cell patch-clamp recordings, we evaluated the sensitivity of rat Nav1.8 (rNav1.8) to BmK I and generated a panel of rNav1.5-based mutants to investigate the functional role of two extra residues (leucine-glutamate, LE) in the DIV/S3-S4 extracellular loop. At 300 nM concentration, BmK I did not significantly slow the inactivation of rNav1.8 (with no significant change in I₅ms/I_peak, P > 0.05). Insertion of LE, or its substitution with leucine-glutamine (LQ), glutamate-histidine (EH), aspartate (D), alanine-alanine (AA), or alanine (A), at the equivalent position of rNav1.5 consistently attenuated BmK I efficacy, yet none of the mutants became completely insensitive. Notably, insertion of alanine produced a similar effect, implicating steric hindrance, rather than side-chain chemistry, as the primary determinant. Conversely, deletion of LE from rNav1.8 fully restored BmK I sensitivity . In marked contrast, the classical α-toxin AaH II still markedly delayed inactivation of both rNav1.5-LE and rNav1.5-AA, revealing that BmK I and AaH II rely on distinct conformational features within receptor site-3. Together, these findings indicate that the length of the DIV/S3-S4 loop, rather than the chemical identity of the inserted residues, is the primary factor correlating with rNav1.8 resistance to BmK I. This correlation is consistent with a steric hindrance mechanism, although direct structural evidence is not provided by the current functional data. Nonetheless, our results offer structural clues for the development of subtype-selective sodium channel modulators.

PMID:
42962901
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.

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