中国科学技术大学曹灿课题组宣布他们开发出途径选择性5-HT1AR激动剂作为一种快速抗抑郁策略。这一研究成果于2025年11月12日发表在国际顶尖学术期刊《细胞》上。
研究小组表征了5-HT1AR的Gi/o亚型信号通路，并确定了其与六种激动剂和三种不同的Gi/o家族蛋白GoA、Gi3和Gz复合物的结构。结合功能分析，课题组阐明了5-HT1AR不同激动剂识别模式和Gi/o亚型信号选择性的机制。
此外，该课题组设计了一种途径选择性激动剂TMU4142，它具有高GoA活性，同时最小化Gi3激活。值得注意的是，TMU4142在无主题抑郁症模型中表现出快速的抗抑郁样作用。总的来说，这些发现表明，根据不同的下游Gi/o信号通路区分异受体和自身受体可能是开发速效抗抑郁药的一个有希望的策略。
研究人员表示，突触前5-HT1AR自受体主要通过Gi3蛋白发出信号，介导反馈抑制，阻碍传统抗抑郁药的治疗效果。相比之下，突触后异受体主要与Go结合，从而促进抗抑郁反应。然而，如何选择性地激活异受体，同时绕过自受体诱导的负反馈仍然是一个重大挑战。
附：英文原文
Title: Pathway-selective 5-HT1AR agonist as a rapid antidepressant strategy
Author: Chunyu Wang, Nan Zhang, Yujie Shao, Tao Li, Mengna Zhang, Meng Gao, Yaqi Liang, Yumeng Wang, Tian Xue, Yiming Shi, He Chen, Can Cao
Issue&Volume: 2025-11-12
Abstract: Presynaptic 5-HT1AR autoreceptors predominantly signal through Gi3 protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic heteroreceptors mainly couple to Go, which promotes antidepressant responses. However, selectively activating heteroreceptors while bypassing the negative feedback induced by autoreceptors remains a significant challenge. Here, we characterized the Gi/o subtype signaling profiles of 5-HT1AR and determined its structures in complex with six agonists and three distinct Gi/o family proteins: GoA, Gi3, and Gz. Combined with functional analysis, we elucidated the mechanisms underlying diverse agonist recognition modes and Gi/o subtype signaling selectivity of 5-HT1AR. Furthermore, we designed a pathway-selective agonist, TMU4142, which exhibits high GoA activity while minimizing Gi3 activation. Remarkably, TMU4142 demonstrated rapid antidepressant-like effects in a mouse model of depression. Collectively, these findings suggest that distinguishing heteroreceptors from autoreceptors based on their distinct downstream Gi/o signaling pathways could be a promising strategy to develop fast-acting antidepressants.
DOI: 10.1016/j.cell.2025.10.022
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01194-8