Protein quality control of N-methyl-D-aspartate receptors.
Protein quality control of N-methyl-D-aspartate receptors.
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DOI：
10.3389/fncel.2022.907560
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发表时间：
2022
影响因子：
5.3
通讯作者：
Wang, Ya-Juan
中科院分区：
文献类型：
--
作者：
Benske, Taylor M.;Mu, Ting-Wei;Wang, Ya-Juan
N-甲基-D-天冬氨酸受体(NMDAR)是谷氨酸门控的阳离子通道，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NMDAR通常通过GluN1和GluN2亚基的异构体组装形成。GRIN基因中的变异与各种神经发育和神经精神障碍有关。由于NMDAR亚单位的组成对突触的区域和发育信号具有重要意义，正确折叠的受体必须到达质膜才能发挥作用。本文就NMDARs的蛋白质质量控制作一综述。具体地说，我们回顾了确保受体在内质网(ER)内正确折叠和组装并运输到质膜的质量控制机制。此外，我们还讨论了NMDAR表面表达和功能受到干扰的疾病相关变异。最后，我们讨论了通过增强携带疾病相关变体的亚单位的表达和表面转运，从而增加它们与功能受体的结合来改善疾病表型的潜在靶向药理和治疗方法。
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 via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN 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.
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