Horak Martin, Barackova Petra, Langore Emily, Netolicky Jakub, Rivas-Ramirez Paula, Rehakova Kristyna
Department of Neurochemistry, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
Front Neurosci. 2021 Mar 16;15:603715. doi: 10.3389/fnins.2021.603715. eCollection 2021.
-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical -glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs.
N-甲基-D-天冬氨酸受体（NMDARs）属于离子型谷氨酸受体家族，在哺乳动物中枢神经系统（CNS）的兴奋性神经传递和突触可塑性中发挥着重要作用。功能性NMDARs由由GluN1、GluN2A-D和/或GluN3A-B亚基组成的异源四聚体构成，每个亚基都包含四个膜结构域（M1至M4）、一个细胞内C末端结构域、一个由氨基末端结构域和配体结合结构域（LBD）的S1片段组成的大的细胞外N末端结构域，以及M3和M4之间的细胞外环，其中包含LBD的S2片段。在细胞表面表达的NMDARs的数量和类型在多个水平上受到调节，包括它们在内质网（ER）中的翻译和翻译后成熟、在高尔基体中的细胞内运输、在质膜中的横向扩散以及内化和降解。本综述重点关注GluN亚基的细胞外区域在ER加工中所起的作用。具体而言，我们讨论了ER保留信号的存在、LBD的完整性以及NMDAR亚基内的关键糖基化位点和二硫键，这些步骤中的每一个都必须在ER中通过质量控制，以确保只有正确组装的NMDARs从ER中释放出来，以便进行后续加工并运输到表面。最后，我们讨论了GluN亚基细胞外结构域内的致病性错义突变对NMDARs的ER加工的影响。
