机制引导下抗抑郁G蛋白偶联受体药物靶点的鉴定，这一成果由威尔康奈尔医学院Conor Liston团队经过不懈努力而取得。2026年4月23日出版的《细胞》杂志发表了这项成果。
该团队破译了速效抗抑郁药氯胺酮的作用机制，从而能够识别G蛋白偶联受体（GPCR）抗抑郁靶点。该研究团队发现氯胺酮的行为效应依赖于多阿片受体（MORs），这些受体在内侧前额叶皮层（mPFC）表达生长抑素的中间神经元（Sst+ INs）中富集。慢性应激导致mPFC Sst+ INs突触前肥大和锥体神经元过度抑制，可通过氯胺酮拯救。在这些发现的激励下，该课题组研究人员进行了RNA测序，以鉴定mPFC Sst+ In富集的GPCR，并验证有希望的靶点的抗抑郁潜力。多种GPCRs的协同靶向使有效的抗抑郁样反应减少了副作用。总之，这些发现揭示了一种确定脑部疾病治疗性GPCR靶点的一般方法。
据悉，抑郁症是由离散神经回路的功能障碍驱动的，但需要更深入地了解潜在的分子和突触机制，以指导治疗方法的发展。
附：英文原文
Title: Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets
Author: Hermany Munguba, Anisul Arefin, Ryota Hasegawa, Luca Posa, Giovanna R. Romano, Teja N. Peddada, Alexander Donatelle, Ashna Singh, Vanessa A. Gutzeit, Akshara Vijay, Prerana Vaddi, Melanie Kristt, Daniel Shaver, Shanjida Hoque, Johannes Broichhagen, Joseph M. Stujenske, Francis S. Lee, Evan O’Brien, Joshua Levitz, Conor Liston
Issue&Volume: 2026-04-23
Abstract: Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics. Here, we decipher the mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on mu-opioid receptors (MORs), which are enriched in somatostatin-expressing interneurons (Sst+ INs) in the medial prefrontal cortex (mPFC). Chronic stress drives presynaptic hypertrophy of mPFC Sst+ INs and excessive inhibition of pyramidal neurons, which is rescued by ketamine. Motivated by these findings, we use RNA sequencing to identify mPFC Sst+ IN-enriched GPCRs and validate the antidepressant potential of promising targets. Synergistic targeting of multiple GPCRs enables potent antidepressant-like responses with reduced side effects. Together, these findings reveal a general approach to identifying therapeutic GPCR targets for brain disorders.
DOI: 10.1016/j.cell.2026.04.006
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00395-8