A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors.
A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors.
复制标题
DOI：
10.1016/j.cub.2009.05.017
复制
发表时间：
2009-06-09
期刊：
影响因子：
--
通讯作者：
Maricq AV
中科院分区：
文献类型：
--
作者：
Walker CS;Jensen S;Ellison M;Matta JA;Lee WY;Imperial JS;Duclos N;Brockie PJ;Madsen DM;Isaac JT;Olivera B;Maricq AV
离子型谷氨酸受体（iGluR）是谷氨酸门控离子通道，其介导中枢神经系统中的兴奋性神经传递。基于分子和药理学标准，iGluR被分为两大类，非NMDA类，包括AMPA和红藻氨酸受体亚型，以及NMDA类。iGluR的一个进化上保守的特征是它们在谷氨酸持续存在下的脱敏。因此，当处于脱敏状态时，iGluR可以与谷氨酸结合，但通道保持关闭。然而，脱敏与神经系统功能的相关性仍然是个谜。在这里，我们报告了一种新的多肽（con-ikot-ikot）的鉴定和表征，从一种捕食性海洋蜗牛Conus striatus的毒液，专门破坏AMPA受体（AMPAR）的脱敏。con-ikot-ikot的化学计量似乎让人想起AMPAR的拟议亚基组织，即，二聚体的二聚体，这表明它作为一个分子四腿钳，保持AMPAR通道开放。将con-ikot-ikot应用于海马切片引起静息AMPAR介导电流的大而快速的增加，导致神经元死亡。我们的研究结果提供了对调节受体脱敏的机制的深入了解，并表明在猎物和捕食者之间的军备竞赛中，进化选择了一种阻止AMPAR脱敏的毒素，从而揭示了脱敏对调节神经功能的根本重要性。
Ionotropic glutamate receptors (iGluRs) are glutamate-gated ion channels that mediate excitatory neurotransmission in the central nervous system. Based on both molecular and pharmacological criteria, iGluRs have been divided into two major classes, the non-NMDA-class, which includes both AMPA and kainate subtypes of receptors, and the NMDA-class. One evolutionarily conserved feature of iGluRs is their desensitization in the continued presence of glutamate. Thus, when in a desensitized state, iGluRs can be bound to glutamate, yet the channel remains closed. However, the relevance of desensitization to nervous system function has remained enigmatic. Here, we report the identification and characterization of a novel polypeptide (con-ikot-ikot) from the venom of a predatory marine snail Conus striatus that specifically disrupts the desensitization of AMPA receptors (AMPARs). The stoichiometry of con-ikot-ikot appears reminiscent of the proposed subunit organization of AMPARs, i.e., a dimer of dimers, suggesting that it acts as a molecular four-legged clamp that holds the AMPAR channel open. Application of con-ikot-ikot to hippocampal slices caused a large and rapid increase in resting AMPAR-mediated current leading to neuronal death. Our findings provide insight into the mechanisms that regulate receptor desensitization, and demonstrate that in the arms race between prey and predators, evolution has selected for a toxin that blocks AMPAR desensitization, thus revealing the fundamental importance of desensitization for regulating neural function.
登录
查看更多内容
影响因子：
5.3
作者：
Partin, KM;Fleck, MW;Mayer, ML
通讯作者：
Mayer, ML
影响因子：
5.7
作者：
Jonas, Peter;Spruston, Nelson
通讯作者：
Spruston, Nelson
影响因子：
9.8
作者：
Ng D;Pitcher GM;Szilard RK;Sertié A;Kanisek M;Clapcote SJ;Lipina T;Kalia LV;Joo D;McKerlie C;Cortez M;Roder JC;Salter MW;McInnes RR
通讯作者：
McInnes RR
影响因子：
5.3
作者：
Herman, Melissa A.;Jahr, Craig E.
通讯作者：
Jahr, Craig E.
影响因子：
56.9
作者：
Heine, Martin;Groc, Laurent;Choquet, Daniel
通讯作者：
Choquet, Daniel