Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220, Prague 4, Czech Republic.
Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220, Prague 4, Czech Republic.
Sci Rep. 2019 Aug 23;9(1):12303. doi: 10.1038/s41598-019-48845-3.
N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that play an essential role in mediating excitatory neurotransmission in the mammalian central nervous system (CNS). Functional NMDARs are tetramers composed of GluN1, GluN2A-D, and/or GluN3A-B subunits, giving rise to a wide variety of NMDAR subtypes with unique functional properties. Here, we examined the surface delivery and functional properties of NMDARs containing mutations in the glycine-binding sites in GluN1 and GluN3A subunits expressed in mammalian cell lines and primary rat hippocampal neurons. We found that the structural features of the glycine-binding sites in both GluN1 and GluN3A subunits are correlated with receptor forward trafficking to the cell surface. In addition, we found that a potentially clinically relevant mutation in the glycine-binding site of the human GluN3A subunit significantly reduces surface delivery of NMDARs. Taken together, these findings provide novel insight into how NMDARs are regulated by their glycine-binding sites and may provide important information regarding the role of NMDARs in both physiological and pathophysiological processes in the mammalian CNS.
N-甲基-D-天冬氨酸受体（NMDARs）是离子型谷氨酸受体，在哺乳动物中枢神经系统（CNS）中介导兴奋性神经传递中起着至关重要的作用。功能性 NMDAR 由 GluN1、GluN2A-D 和/或 GluN3A-B 亚基组成四聚体，产生具有独特功能特性的多种 NMDAR 亚型。在这里，我们研究了在哺乳动物细胞系和原代大鼠海马神经元中表达的 GluN1 和 GluN3A 亚基中甘氨酸结合位点突变的 NMDAR 的表面递呈和功能特性。我们发现 GluN1 和 GluN3A 亚基中甘氨酸结合位点的结构特征与受体正向转运到细胞表面相关。此外，我们发现人类 GluN3A 亚基甘氨酸结合位点的一个潜在临床相关突变显著降低了 NMDAR 的表面递呈。总之，这些发现为 NMDAR 如何受其甘氨酸结合位点调节提供了新的见解，并可能为 NMDAR 在哺乳动物 CNS 中的生理和病理生理过程中的作用提供重要信息。
