▎药明康德团队  

甘氨酸

是中枢神经系统中重要的神经递质。在甘氨酸能神经元的抑制性突触中，甘氨酸通过激活甘氨酸受体，控制呼吸节律、肌张力、运动协调并参与中枢神经系统的早期发育；在谷氨酸能神经元的兴奋性突触中，甘氨酸作为共激动剂参与NMDA受体的激活，调控学习与记忆活动。

突触间隙中的甘氨酸浓度由两种

甘氨酸转运蛋白（glycine transporter, GlyT）GlyT1和GlyT2进行调控，以保证突触前和突触后活动的严格平衡。GlyT1和GlyT2在神经网络中的分布和功能不同。在抑制性神经元的突触间隙中，甘氨酸主要由GlyT2回收，而在兴奋性神经元的突触间隙中，NMDA受体附近甘氨酸的浓度主要由GlyT1调节。

精神分裂症（schizophrenia）是一种高致残率的精神疾病，至少困扰世界上约1%的人口。其临床特征为阳性症状（幻觉、妄想）、阴性症状（情绪扁平、社交失能）和认知障碍。阳性症状目前已有临床药物进行治疗，而长期影响患者社会功能和生活质量的阴性症状和认知障碍仍缺乏有效的治疗手段。

图片来源：123RF

大量研究支持NMDA受体的功能减退是致病机制之一，增强NMDA受体的功能有潜力治疗精神分裂症阴性症状和认知障碍。虽然直接口服NMDA受体激动剂甘氨酸可以显著减轻阴性症状、改善认知能力，但由于用药剂量高、治疗窗口期窄、中枢神经系统渗透率差、以及伴随而来的副作用和潜在的药物相互作用等而应用受限。

由于GlyT1与NMDA受体高度共定位，抑制GlyT1可以提高突触间隙的甘氨酸浓度，促进NMDA受体激活。因此，GlyT1被认为是治疗精神分裂症的关键靶点之一，多家制药企业开发了选择性抑制GlyT1的化合物作为精神分裂症的候选治疗药物，并开展了大量临床研究。而探究GlyT1底物识别、离子结合、构象变化以及与其它临床试验药物分子之间的构效关系，有助于加速靶向GlyT1的药物开发进程。

2024年3月21日，中国科学院生物物理研究所赵岩研究组在《细胞》（

Cell）发表了题为“Transport mechanism and pharmacology of the human GlyT1”的研究论文。研究人员解析了人源全长野生型GlyT1转运过程中的三种不同构象，并鉴定了底物甘氨酸、基于肌氨酸（sarcosine based）的抑制剂ALX-5407以及基于非肌氨酸（non-sarcosine based）的抑制剂SSR504734和PF-03463275共四种配体的结合位点，

首次阐明GlyT1的底物识别和三种抗精神分裂候选药物选择性抑制GlyT1的机制。

GlyT1所属的SLC6家族神经递质转运蛋白的功能都依赖钠离子和氯离子。研究团队在分辨率为2.6 Å的封闭态GlyT1电镜结构中发现了底物甘氨酸的结合，同时鉴定了共转运的一个氯离子与两个钠离子的结合位点，阐释了底物与离子结合及转运的偶联关系。通过对比其他神经递质转运蛋白的中央结合腔及离子结合位点，研究团队识别出其中的关键差异残基，并对构成GlyT1底物和离子结合口袋的保守残基和差异残基进行了功能鉴定。

▲GlyT1生理和药理的分子机制

（图片来源：参考资料[1]）

研究团队全面揭示了决定这些化合物选择性抑制GlyT1而非GlyT2的分子机理。

此外，通过对比外向开口、封闭、内向开口三种不同构象的电镜结构，研究团队系统性阐述了分别稳定外向开口构象和内向开口构象的关键相互作用网络，丰富了对神经递质转运蛋白构象变化机制的理解。

中国科学院生物物理研究所赵岩研究员为该论文通讯，中国科学院生物物理研究所博士研究生魏一青、黎仁杰、孟宇飞、胡拓和北京大学现代农业研究院赵珺研究员为论文的共同第一。此外，生物物理所博士研究生高逸伟、白秦儒和首都医科大学附属北京朝阳医院李娜也为本研究提供了帮助。本研究得到科技创新2030"脑科学与类脑研究"重大项目、国家重点研发计划项目、中国科学院战略性先导科技专项（B类）、国家自然科学基金项目等项目的资助。冷冻电镜数据收集得到中国科学院生物物理研究所蛋白质科学研究平台生物成像中心、北京大学现代农业研究院生物微观结构研究平台的技术支持。放射性转运实验得到中国科学院生物物理研究所放射性同位素实验室的帮助。

中科院生物物理所赵岩课题组开展神经信号传递的分子机制研究，在

Nature、

Cell、

Science、

NSMB等期刊上发表了多篇研究论文。赵岩课题组长期招聘优秀博士后和实验员，有意者可将个人详细简历和推荐人（2～3位）联系方式以及其它相关材料进行投递。

参考资料：

[1] Wei et al. Transport mechanism and pharmacology of the human GlyT1.

Cell (2024). DOI: 10.1016/j.cell.2024.02.026

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