Carbone Anna L, Plested Andrew J R
Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straβe 10, 13125 Berlin, Germany.
NeuroCure, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Nat Commun. 2016 Jan 8;7:10178. doi: 10.1038/ncomms10178.
Glutamate receptors form complexes in the brain with auxiliary proteins, which control their activity during fast synaptic transmission through a seemingly bewildering array of effects. Here we devise a way to isolate the activation of complexes using polyamines, which enables us to show that transmembrane AMPA receptor regulatory proteins (TARPs) exert their effects principally on the channel opening reaction. A thermodynamic argument suggests that because TARPs promote channel opening, receptor activation promotes AMPAR-TARP complexes into a superactive state with high open probability. A simple model based on this idea predicts all known effects of TARPs on AMPA receptor function. This model also predicts unexpected phenomena including massive potentiation in the absence of desensitization and supramaximal recovery that we subsequently detected in electrophysiological recordings. This transient positive feedback mechanism has implications for information processing in the brain, because it should allow activity-dependent facilitation of excitatory synaptic transmission through a postsynaptic mechanism.
谷氨酸受体在大脑中与辅助蛋白形成复合物，这些辅助蛋白在快速突触传递过程中通过一系列看似令人困惑的效应来控制其活性。在这里，我们设计了一种利用多胺来分离复合物激活的方法，这使我们能够表明跨膜AMPA受体调节蛋白（TARPs）主要对通道开放反应发挥作用。一个热力学观点表明，由于TARPs促进通道开放，受体激活会促使AMPA受体 - TARPs复合物进入具有高开放概率的超激活状态。基于这一想法的一个简单模型预测了TARPs对AMPA受体功能的所有已知效应。该模型还预测了一些意外现象，包括在无脱敏情况下的大量增强以及我们随后在电生理记录中检测到的超最大恢复。这种瞬时正反馈机制对大脑中的信息处理具有重要意义它应该允许通过突触后机制对兴奋性突触传递进行活动依赖性促进。
