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Toxicon. 2016 Mar 1;111:13-21. doi: 10.1016/j.toxicon.2015.12.009. Epub 2015 Dec 23.

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

Author information

1
Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China; Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha 410208, Hunan, China. Electronic address: taohuai123@126.com.
2
Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
3
Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China.
4
State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha 410013, Hunan, China.
5
Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China. Electronic address: liangsp@hunnu.edu.cn.

Abstract

Peptide toxins often have divergent pharmacological functions and are powerful tools for a deep review on the current understanding of the structure-function relationships of voltage-gated sodium channels (VGSCs). However, knowing about the interaction of site 3 toxins from tarantula venoms with VGSCs is not sufficient. In the present study, using whole-cell patch clamp technique, we determined the effects of Jingzhaotoxin-I (JZTX-I) on five VGSC subtypes expressed in HEK293 cells. The results showed that JZTX-I could inhibit the inactivation of rNav1.2, rNav1.3, rNav1.4, hNav1.5 and hNav1.7 channels with the IC50 of 870 ± 8 nM, 845 ± 4 nM, 339 ± 5 nM, 335 ± 9 nM, and 348 ± 6 nM, respectively. The affinity of the toxin interaction with subtypes (rNav1.4, hNav1.5, and hNav1.7) was only 2-fold higher than that for subtypes (rNav1.2 and rNav1.3). The toxin delayed the inactivation of VGSCs without affecting the activation and steady-state inactivation kinetics in the physiological range of voltages. Site-directed mutagenesis indicated that the toxin interacted with site 3 located at the extracellular S3-S4 linker of domain IV, and the acidic residue Asp at the position1609 in hNav1.5 was crucial for JZTX-I activity. Our results provide new insights in single key residue that allows toxins to recognize distinct ion channels with similar potency and enhance our understanding of the structure-function relationships of toxin-channel interactions.

KEYWORDS:

Inactivation; Jingzhaotoxin-I; Mutation; Voltage-gated sodium channels

PMID:
26721415
DOI:
10.1016/j.toxicon.2015.12.009
[Indexed for MEDLINE]

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