Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a) Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

被引:11
|
作者
Luo, Ji [1 ]
Zhang, Yiya [1 ]
Gong, Mengting [1 ]
Lu, Shanshan [1 ]
Ma, Yifeng [1 ]
Zeng, Xiongzhi [1 ]
Liang, Songping [1 ]
机构
[1] Hunan Normal Univ, Coll Life Sci, Key Lab Prot Chem & Dev Biol, Minist Educ, Changsha 410081, Hunan, Peoples R China
来源
TOXINS | 2014年 / 6卷 / 07期
关键词
spider toxin; voltage gated sodium channels; JZTX-V; Na(V)1.4; SPIDER-VENOM PEPTIDES; NERVOUS-SYSTEM; NEURONS; TOXINS; RAT; LOCALIZATION; MODULATION; ACTIVATION; EXPRESSION; ISOFORMS;
D O I
10.3390/toxins6072177
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
Voltage-gated sodium channels (VGSCs; Na(V)1.1-Na(V)1.9) have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure-function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX)-V (also known as beta-theraphotoxin-Cj2a) is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK) motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7-2700 nM for other heterologously expressed Na(V)1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on Na(V)1.4 and demonstrate that the bioactive face of JZTX- V is composed of three hydrophobic (W5, M6, and W7) and two cationic (R20 and K22) residues. Our results establish that, consistent with previous assumptions, JZTX- V is a Janus- faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.
引用
收藏
页码:2177 / 2193
页数:17
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