Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Mol Brain. 2020 Feb 18;13(1):23. doi: 10.1186/s13041-020-0563-z.
N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamatergic receptors that are fundamental for many neuronal processes, including synaptic plasticity. NMDARs are comprised of four subunits derived from heterogeneous subunit families, yielding a complex diversity in NMDAR form and function. The quadruply-liganded state of binding of two glutamate and two glycine molecules to the receptor drives channel gating, allowing for monovalent cation flux, Ca entry and the initiation of Ca-dependent signalling. In addition to this ionotropic function, non-ionotropic signalling can be initiated through the exclusive binding of glycine or of glutamate to the NMDAR. This binding may trigger a transmembrane conformational change of the receptor, inducing intracellular protein-protein signalling between the cytoplasmic domain and secondary messengers. In this review, we outline signalling cascades that can be activated by NMDARs and propose that the receptor transduces signalling through three parallel streams: (i) signalling via both glycine and glutamate binding, (ii) signalling via glycine binding, and (iii) signalling via glutamate binding. This variety in signal transduction mechanisms and downstream signalling cascades complements the widespread prevalence and rich diversity of NMDAR activity throughout the central nervous system and in disease pathology.
N-甲基-D-天冬氨酸受体（NMDARs）是兴奋性谷氨酸受体，对于许多神经元过程至关重要，包括突触可塑性。NMDAR 由四个亚基组成，这些亚基来自不同的亚基家族，导致 NMDAR 形式和功能的复杂多样性。两个谷氨酸和两个甘氨酸分子与受体的四重配体结合状态驱动通道门控，允许单价阳离子流、Ca 进入和 Ca 依赖性信号的起始。除了这种离子型功能外，非离子型信号可以通过甘氨酸或谷氨酸对 NMDAR 的专有结合来启动。这种结合可能引发受体的跨膜构象变化，在细胞质结构域和二级信使之间诱导细胞内蛋白-蛋白信号转导。在这篇综述中，我们概述了可以被 NMDAR 激活的信号级联，并提出该受体通过三个平行的信号流转导信号：（i）通过甘氨酸和谷氨酸结合进行信号转导，（ii）通过甘氨酸结合进行信号转导，以及（iii）通过谷氨酸结合进行信号转导。这种信号转导机制和下游信号级联的多样性补充了 NMDAR 活性在中枢神经系统和疾病病理学中的广泛存在和丰富多样性。
