Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; IdiPAZ, Institute of Health Carlos III (ISCIII), Spain.
Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; IdiPAZ, Institute of Health Carlos III (ISCIII), Spain.
Neuropharmacology. 2023 Jul 1;232:109514. doi: 10.1016/j.neuropharm.2023.109514. Epub 2023 Mar 31.
NMDA-type glutamate receptors (NMDARs) constitute one of the main glutamate (Glu) targets in the central nervous system and are involved in synaptic plasticity, which is the molecular substrate of learning and memory. Hypofunction of NMDARs has been associated with schizophrenia, while overstimulation causes neuronal death in neurodegenerative diseases or in stroke. The function of NMDARs requires coincidental binding of Glu along with other cellular signals such as neuronal depolarization, and the presence of other endogenous ligands that modulate their activity by allosterism. Among these allosteric modulators are zinc, protons and Gly, which is an obligatory co-agonist. These characteristics differentiate NMDARs from other receptors, and their structural bases have begun to be established in recent years. In this review we focus on the crosstalk between Glu and glycine (Gly), whose concentration in the NMDAR microenvironment is maintained by various Gly transporters that remove or release it into the medium in a regulated manner. The GlyT1 transporter is particularly involved in this task, and has become a target of great interest for the treatment of schizophrenia since its inhibition leads to an increase in synaptic Gly levels that enhances the activity of NMDARs. However, the only drug that has completed phase III clinical trials did not yield the expected results. Notwithstanding, there are additional drugs that continue to be investigated, and it is hoped that knowledge gained from the recently published 3D structure of GlyT1 may allow the rational design of more effective new drugs. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）是中枢神经系统中主要的谷氨酸（Glu）靶点之一，参与突触可塑性，这是学习和记忆的分子基础。NMDAR 功能低下与精神分裂症有关，而过激则会导致神经退行性疾病或中风中的神经元死亡。NMDAR 的功能需要 Glu 与其他细胞信号（如神经元去极化）同时结合，并且存在其他内源性配体通过变构作用来调节其活性。这些变构调节剂包括锌、质子和甘氨酸（Gly），它是必需的共激动剂。这些特性使 NMDAR 有别于其他受体，其结构基础近年来已开始建立。在这篇综述中，我们重点讨论 Glu 和甘氨酸（Gly）之间的串扰，其在 NMDAR 微环境中的浓度由各种 Gly 转运体维持，这些转运体以受调控的方式将其去除或释放到介质中。GlyT1 转运体特别参与了这一任务，并且由于其抑制作用会导致突触 Gly 水平增加，从而增强 NMDAR 的活性，因此已成为治疗精神分裂症的重要靶点。然而，唯一完成 III 期临床试验的药物并未产生预期的结果。尽管如此，还有其他药物仍在继续研究中，希望最近发表的 GlyT1 3D 结构所获得的知识可以允许合理设计更有效的新药。本文是“受体-受体相互作用作为治疗新靶点”特刊的一部分。
