The action of Con-ikot-ikot toxin on single AMPA-type glutamate receptors.
The action of Con-ikot-ikot toxin on single AMPA-type glutamate receptors.
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DOI：
10.1085/jgp.202112912
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发表时间：
2022-05-02
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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巴拉诺维奇等人。描述刀芋螺毒素如何调节AMPA受体的活性，AMPA受体是兴奋性神经传递的主要媒介。Con-Ikot-Ikot可以阻断AMPA受体的脱敏，如环噻嗪和(R，R)-2b，但与它们不同的是，它是完全开放通道的糟糕稳定剂。芋螺毒素是一大类天然存在的有毒多肽，由螺螺属的捕食性海螺产生。其中许多毒素以离子通道为靶标，通常具有高度的特异性和亲和力。因此，它们已被证明对基础研究以及治疗策略起到了无价的指导作用。Con-Ikot-Ikot是迄今为止发现的唯一一种以AMPA型谷氨酸受体为靶标的芋螺毒素，AMPA型谷氨酸受体是脊椎动物大脑中兴奋性神经传递的主要介质。在这里，我们描述了毒素如何在单通道水平上改变AMPA受体的活性。这种毒素与AMPA受体结合，EC50为5 NM，一旦结合，需要几分钟才能洗掉。如前所述，它有效地阻断了AMPA受体的脱敏；然而，与其他脱敏阻滞剂相比，它是开放通道的较差稳定剂，因为毒素结合的AMPA受体经常经历短暂的关闭。我们认为这是毒素与配体结合域(LBD)独特的结合模式的直接结果。与其他脱敏阻滞剂不同的是，这种毒素可以固定AMPA受体四聚体中的所有四个LBD，从而稳定AMPA受体四聚体中的单个二聚体。这一结果进一步强调了独立的LBD二聚体的季度性重组对于AMPA受体的充分活性是必不可少的。
Baranovic et al. describe how Con-ikot-ikot conotoxin modulates the activity of AMPA receptors, major mediators of excitatory neurotransmission. Con-ikot-ikot blocks AMPA receptor desensitization, like cyclothiazide and (R, R)-2b, but unlike them it is a poor stabilizer of the fully open channel. Conotoxins are a large group of naturally occurring toxic peptides produced by the predatory sea snails of the genus Conus. Many of these toxins target ion channels, often with high specificity and affinity. As such, they have proven to be invaluable for basic research, as well as acting as leads for therapeutic strategies. Con-ikot-ikot is the only conotoxin so far identified that targets AMPA-type glutamate receptors, the main mediators of excitatory neurotransmission in the vertebrate brain. Here, we describe how the toxin modifies the activity of AMPA receptors at the single-channel level. The toxin binds to the AMPA receptor with EC50 of 5 nM, and once bound takes minutes to wash out. As shown previously, it effectively blocks desensitization of AMPA receptors; however, compared to other desensitization blockers, it is a poor stabilizer of the open channel because toxin-bound AMPA receptors undergo frequent brief closures. We propose that this is a direct consequence of the toxin’s unique binding mode to the ligand-binding domains (LBDs). Unlike other blockers of desensitization, which stabilize individual dimers within an AMPA receptor tetramer, the toxin immobilizes all four LBDs of the tetramer. This result further emphasizes that quaternary reorganization of independent LBD dimers is essential for the full activity of AMPA receptors.
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AMPA受体GLUA2在休息，预开口和脱敏状态中的结构和动力学。
影响因子：
64.5
作者：
Dürr KL;Chen L;Stein RA;De Zorzi R;Folea IM;Walz T;Mchaourab HS;Gouaux E
通讯作者：
Gouaux E
影响因子：
16.2
作者：
Dawe GB;Musgaard M;Aurousseau MRP;Nayeem N;Green T;Biggin PC;Bowie D
通讯作者：
Bowie D
DOI：
10.1523/jneurosci.5613-09.2010
发表时间：
2010-03-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Prieto ML;Wollmuth LP
通讯作者：
Wollmuth LP
影响因子：
3.4
作者：
Baranovic, Jelena;Chebli, Miriam;Plested, Andrew J. R.
通讯作者：
Plested, Andrew J. R.
影响因子：
5.3
作者：
Partin, KM;Fleck, MW;Mayer, ML
通讯作者：
Mayer, ML