2024年5月22日，美国哥伦比亚大学Alexander I. Sobolevsky研究小组在《自然》杂志发表论文，破译出kainate受体通道开放和门控机制。

研究人员展示了在激动剂谷氨酸以及正变构调节剂凝集素伴刀豆球蛋白A和BPAM344作用下的，kainate受体GluK2的冷冻电镜结构。凝集素A和BPAM344分别作为氨基末端结构域和配体结合结构域之间的，间隔物和配体结合结构域二聚体界面的稳定剂，抑制了kainate受体的脱敏并延长了其激活时间。通道开放涉及所有四个形成孔的M3螺旋的扭结。这些结构揭示了kainate受体门控的分子基础，可以指导治疗神经系统疾病药物的开发。

据了解，kainate受体是离子型谷氨酸受体的一个亚类，是四聚体配体门控离子通道，介导兴奋性神经传递。kainate受体在中枢神经系统的发育和功能过程中调节神经元回路和突触可塑性，并与多种神经和精神疾病有关，包括癫痫、抑郁症、精神分裂症、焦虑症和自闭症。虽然目前已有kainate受体结构域和亚基组合的结构，但人们对kainate受体的门控机制仍然知之甚少。

附：英文原文

Title: Kainate receptor channel opening and gating mechanism

Author: Gangwar, Shanti Pal, Yelshanskaya, Maria V., Nadezhdin, Kirill D., Yen, Laura Y., Newton, Thomas P., Aktolun, Muhammed, Kurnikova, Maria G., Sobolevsky, Alexander I.

Issue&Volume: 2024-05-22

Abstract: Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1,2,3,4. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism5,6,7,8,9,10,11. Although structures of kainate receptor domains and subunit assemblies are available12,13,14,15,16,17,18, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.

DOI: 10.1038/s41586-024-07475-0

Source: https://www.nature.com/articles/s41586-024-07475-0