Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission^1,2,3,4. 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 autism^{5,6,7,8,9,10,11}. Although structures of kainate receptor domains and subunit assemblies are available^{12,13,14,15,16,17,18}, 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.

红藻氨酸受体是离子型谷氨酸受体的一个亚类，是介导兴奋性神经传递的四聚体配体门控离子通道^1,2,3,4。红藻氨酸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，并与各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^{5,6,7,8,9,10,11}。尽管红藻氨酸受体结构域和亚基组装体的结构可用^{12,13,14,15,16,17,18}，但红藻氨酸受体门控的机制仍然知之甚少。在这里，我们展示了在激动剂谷氨酸和正变构调节剂凝集素伴刀豆球蛋白 A 和 BPAM344 存在下红藻酸盐受体 GluK2 的冷冻电子显微镜结构。伴刀豆球蛋白 A 和 BPAM344 分别充当氨基末端和配体结合结构域之间的间隔区以及配体结合结构域二聚体界面的稳定剂，从而抑制红藻氨酸受体脱敏并延长活化。通道开放涉及所有四个成孔 M3 螺旋的扭结。我们的结构揭示了红藻氨酸受体门控的分子基础，这可以指导治疗神经系统疾病的药物开发。