蜘蛛毒素诱导乙酰胆碱受体的快速脱敏。

Na Clara Pan, Tingting Zhang, Shimin Hu, Chunyan Liu, Yuping Wang
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引用次数: 3

摘要

烟碱乙酰胆碱受体(Nicotinic acetylcholine receptor, nAChRs)是“cys-loop”配体门控离子通道超家族的成员,在外周和中枢系统中都起着重要作用。在神经肌肉连接处,ACh结合和nAChR激活诱导终板电流,然后,电流下降到一个小的稳态,尽管ACh仍然与受体结合。对乙酰胆碱具有高亲和力但没有可测量的离子电导率的nachr的动力学称为脱敏。这种采用的nAChR通道电流脱敏可能是保护细胞免受不受控制的激励的重要机制。本研究旨在证明首次从狼蛛Grammostola spatulata(现属Phixotricus)的毒液中纯化并鉴定的Grammostola spatulata毒素(GsMTx4)能够促进小鼠C2C12肌管中nAChRs的脱敏。为了研究细节,研究了HEK293T细胞中异种表达的肌肉型nachr。在细胞连接配置下记录了单通道电流,并且在移液管溶液中加入GsMTx-4后,通道活性(NPo)衰减得更快。进一步分析了通道动力学,发现GsMTx-4通过延长关闭时间而不影响通道电导或打开活性来影响nAChRs的通道活性。嵌入脂质膜内的nachr与嵌入膜内的毒素之间的相互作用可能导致受体的构象改变,从而改变通道活性。GsMTx-4的这一新特性可能有助于更好地理解配体门控通道的脱敏和疾病治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Fast desensitization of acetylcholine receptors induced by a spider toxin.

Fast desensitization of acetylcholine receptors induced by a spider toxin.

Fast desensitization of acetylcholine receptors induced by a spider toxin.

Fast desensitization of acetylcholine receptors induced by a spider toxin.

Nicotinic acetylcholine receptors (nAChRs) are members of the "cys-loop" ligand-gated ion channel superfamily that play important roles in both the peripheral and central system. At the neuromuscular junction, the endplate current is induced by ACh binding and nAChR activation, and then, the current declines to a small steady state, even though ACh is still bound to the receptors. The kinetics of nAChRs with high affinity for ACh but no measurable ion conductance is called desensitization. This adopted desensitization of nAChR channel currents might be an important mechanism for protecting cells against uncontrolled excitation. This study aimed to show that Grammostola spatulata toxin (GsMTx4), which was first purified and characterized from the venom of the tarantula Grammostola spatulata (now genus Phixotricus), can facilitate the desensitization of nAChRs in murine C2C12 myotubes. To examine the details, muscle-type nAChRs, which are expressed heterologously in HEK293T cells, were studied. A single channel current was recorded under the cell-attached configuration, and the channel activity (NPo) decayed much faster after the addition of GsMTx-4 to the pipette solution. The channel kinetics were further analyzed, and GsMTx-4 affected the channel activity of nAChRs by prolonging the closing time without affecting channel conductance or opening activity. The interaction between nAChRs embedded in the lipid membrane and toxin inserted into the membrane may contribute to the conformational change in the receptor and thus change the channel activity. This new property of GsMTx-4 may lead to a better understanding of the desensitization of ligand-gated channels and disease therapy.

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