A Novel Spider Toxin Inhibits Fast Inactivation of the Na(v)1.9 Channel by Binding to Domain III and Domain IV Voltage Sensors.
A Novel Spider Toxin Inhibits Fast Inactivation of the Na(v)1.9 Channel by Binding to Domain III and Domain IV Voltage Sensors.
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一种新型蜘蛛毒素通过与域 III 和域 IV 电压传感器结合来抑制 Nav1.9 通道的快速失活
DOI：
10.3389/fphar.2021.778534
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发表时间：
2021
影响因子：
5.6
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Peng S;Chen M;Xiao Z;Xiao X;Luo S;Liang S;Zhou X;Liu Z
有毒动物已经进化到产生肽毒素，调节电压门控钠（Nav）通道的活性。这些特异性调节剂是研究Nav通道结构和功能特征的有力探针。在这里，我们报告的δ-theraphotoxin-Gr 4 b（Gr 4 b），一种新的肽毒素从蜘蛛Grammostola rosea毒液的分离和表征。Gr 4 b含有37个氨基酸残基，其中6个半胱氨酸形成3个二硫键。膜片钳分析证实Gr 4 b显著减慢Nav1.9的快速失活，抑制Nav1.4和Nav1.7的电流，但不影响Nav1.8。研究还发现，Gr 4 b使Nav1.9的稳态激活和失活曲线显著向去极化方向移动，并增加窗口电流，这与斜坡电流的变化一致。此外，Nav1.9/Nav1.8嵌合通道的分析显示，Gr 4 b优先结合域III的电压传感器（DIII VSD），并与DIV VSD有额外的相互作用。定点突变分析表明，DIII S3-S4接头中的N1139和L1143参与毒素结合。总之，本研究报告了一种新的蜘蛛肽毒素，它可能通过与新的神经毒素受体位点DIII VSD结合来减缓Nav1.9的快速失活。总之，这些研究结果提供了深入了解的导航通道DIII VSD的快速失活和激活的功能作用。
Venomous animals have evolved to produce peptide toxins that modulate the activity of voltage-gated sodium (Nav) channels. These specific modulators are powerful probes for investigating the structural and functional features of Nav channels. Here, we report the isolation and characterization of δ-theraphotoxin-Gr4b (Gr4b), a novel peptide toxin from the venom of the spider Grammostola rosea. Gr4b contains 37-amino acid residues with six cysteines forming three disulfide bonds. Patch-clamp analysis confirmed that Gr4b markedly slows the fast inactivation of Nav1.9 and inhibits the currents of Nav1.4 and Nav1.7, but does not affect Nav1.8. It was also found that Gr4b significantly shifts the steady-state activation and inactivation curves of Nav1.9 to the depolarization direction and increases the window current, which is consistent with the change in the ramp current. Furthermore, analysis of Nav1.9/Nav1.8 chimeric channels revealed that Gr4b preferentially binds to the voltage-sensor of domain III (DIII VSD) and has additional interactions with the DIV VSD. The site-directed mutagenesis analysis indicated that N1139 and L1143 in DIII S3-S4 linker participate in toxin binding. In sum, this study reports a novel spider peptide toxin that may slow the fast inactivation of Nav1.9 by binding to the new neurotoxin receptor site-DIII VSD. Taken together, these findings provide insight into the functional role of the Nav channel DIII VSD in fast inactivation and activation.
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DOI：
10.1155/2012/731293
发表时间：
2012
期刊：
International journal of peptides
影响因子：
--
作者：
Kimura T;Ono S;Kubo T
通讯作者：
Kubo T
影响因子：
4.2
作者：
Chen R;Robinson A;Chung SH
通讯作者：
Chung SH
DOI：
10.1073/pnas.95.15.8963
发表时间：
1998-07-21
影响因子：
11.1
作者：
Dib-Hajj, SD;Tyrrell, L;Waxman, SG
通讯作者：
Waxman, SG
DOI：
10.1093/brain/awu015
发表时间：
2014-04
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Groome JR;Lehmann-Horn F;Fan C;Wolf M;Winston V;Merlini L;Jurkat-Rott K
通讯作者：
Jurkat-Rott K
DOI：
10.1085/jgp.201611678
发表时间：
2017-03-06
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hsu EJ;Zhu W;Schubert AR;Voelker T;Varga Z;Silva JR
通讯作者：
Silva JR