Li Yan, Dharkar Poorva, Han Tae-Hee, Serpe Mihaela, Lee Chi-Hon, Mayer Mark L
Program in Cellular Regulation and Metabolism, NICHD, NIH, Bethesda, MD 20892, USA.
Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, MD 20892, USA.
Neuron. 2016 Dec 7;92(5):1036-1048. doi: 10.1016/j.neuron.2016.10.058. Epub 2016 Nov 23.
Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation. VIDEO ABSTRACT.
系统发育分析揭示了昆虫基因组中的AMPA、海人酸和NMDA受体家族，这表明它们具有与脊椎动物对应受体保守的功能特性。然而，果蝇海人酸受体DKaiR1D和AMPA受体DGluR1A的异源表达揭示了新的配体选择性，这与用于脊椎动物谷氨酸受体离子通道（iGluRs）的分类不一致。DKaiR1D形成一种快速激活和脱敏的受体，它被NMDA和NMDA受体拮抗剂AP5抑制；DKaiR1D配体结合域的晶体结构显示，这些配体稳定开放裂隙构象，解释了它们作为拮抗剂的作用。令人惊讶的是，AMPA受体DGluR1A对其同名激动剂AMPA以及对quisqualate的激活作用较弱。DGluR1A配体结合域的晶体结构揭示了干扰这些配体结合的氨基酸交换。昆虫iGluRs意外的配体结合谱使得经典工具可用于研究突触调节的新方法中。视频摘要。
