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Abstract：
Neurotransmission mediated by diverse subtypes of N-methyl-D-aspartate receptors (NMDARs) is fundamental for basic brain functions and development as well as neuropsychiatric diseases and disorders. NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B). The GluN2C and GluN2D subunits form ion channels with distinct properties and spatio-temporal expression patterns. Here, we provide the structures of the agonist-bound human GluN1-2C NMDAR in the presence and absence of the GluN2C-selective positive allosteric potentiator (PAM), PYD-106, the agonist-bound GluN1-2A-2C tri-heteromeric NMDAR, and agonist-bound GluN1-2D NMDARs by single-particle electron cryomicroscopy. Our analysis shows unique inter-subunit and domain arrangements of the GluN2C NMDARs, which contribute to functional regulation and formation of the PAM binding pocket and is distinct from GluN2D NMDARs. Our findings here provide the fundamental blueprint to study GluN2C- and GluN2D-containing NMDARs, which are uniquely involved in neuropsychiatric disorders.
摘要：
由N-甲基-D-天冬氨酸受体（NMDARs）的不同亚型介导的神经传递是基本脑功能和发育以及神经精神疾病和障碍的基础。NMDAR是甘氨酸和谷氨酸门控离子通道，以异四聚体的形式存在，由强制性GluN1和GluN2（A-D）和/或GluN3（A-B）组成。GluN2C和GluN2D亚基形成具有不同性质和时空表达模式的离子通道。这里,我们提供了在存在和不存在GluN2C选择性正变构增效剂（PAM）的情况下，激动剂结合的人GluN1-2CNMDAR的结构，PYD-106，激动剂结合的GluN1-2A-2C三异聚NMDAR，和激动剂结合的GluN1-2DNMDARs通过单粒子电子冷冻显微镜。我们的分析显示了GluN2CNMDAR的独特亚基间和结构域排列，它有助于PAM结合口袋的功能调节和形成，与GluN2DNMDAR不同。我们的发现为研究含GluN2C和GluN2D的NMDAR提供了基础蓝图，与神经精神疾病有独特的关系。
