Benske Taylor M, Mu Ting-Wei, Wang Ya-Juan
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States.
Front Cell Neurosci. 2022 Jul 22;16:907560. doi: 10.3389/fncel.2022.907560. eCollection 2022.
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors.
N-甲基-D-天冬氨酸受体（NMDARs）是谷氨酸门控阳离子通道，介导兴奋性神经传递，对哺乳动物中枢神经系统（CNS）的突触发育和可塑性至关重要。功能性NMDARs通常由GluN1和GluN2亚基形成异源四聚体组装。基因内的变体与各种神经发育和神经精神疾病有关。由于NMDAR亚基组成对突触区域和发育信号传导的重要性，正确折叠的受体必须到达质膜才能发挥其功能。本综述聚焦于NMDARs的蛋白质质量控制。具体而言，我们综述了确保受体在内质网（ER）中正确折叠和组装并转运到质膜的质量控制机制。此外，我们讨论了已显示破坏NMDAR表面表达和功能的疾病相关变体。最后，我们讨论了潜在的靶向药理学和治疗方法，通过增强携带疾病相关变体的亚基的表达和表面转运来改善疾病表型，从而增加它们整合到功能性受体中的比例。
