Zhang Xuan, Cai Wensheng, Wang Chao, Tian Jing
Institute of Brain Disease and Data Analysis, College of Life Sciences and Oceanography, Shenzhen University, 518060, Guangdong, PR China.
Chemical Analysis & Physical Testing Institute, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, Guang Dong, PR China.
Pharmacol Ther. 2025 Sep;273:108888. doi: 10.1016/j.pharmthera.2025.108888. Epub 2025 May 22.
N-methyl-D-aspartate receptors (NMDARs) are a class of calcium-permeable ion channel that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confers biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDARs with high efficacy and low toxicity for treating brain disorders associated with NMDARs abnormalities. In this review, we summarize both mechanism research and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our aim is to provide new insights for innovative drug development.
N-甲基-D-天冬氨酸受体（NMDARs）是一类钙通透性离子通道，广泛分布于全身，由多种亚基组成。受体存在多种配体以及亚细胞定位赋予了其偏向性信号传导和独特的功能作用。NMDARs的激活会诱导钙内流，这在神经递质释放、突触可塑性和细胞内信号传导中起关键作用。NMDARs在突触和突触外位点的差异定位导致不同的生理效应；NMDARs的过度激活或激活不足会破坏钙稳态，导致神经元损伤以及随后的神经功能障碍和相关疾病。因此，开发高效低毒的靶向NMDARs的药物对于治疗与NMDARs异常相关的脑部疾病至关重要。在本综述中，我们总结了关于NMDARs的机制研究和临床研究，同时讨论了旨在通过调节机制、亚基重排、膜表达以及突触与突触外NMDARs的特异性靶向来调节离子通道活性的潜在治疗靶点。我们的目的是为创新药物开发提供新的见解。
