芬兰赫尔辛基大学Eero Castrén团队发现，抗抑郁药通过直接结合TRKB神经营养蛋白受体来发挥作用。这一研究成果于2021年2月18日在线发表在国际学术期刊《细胞》上。
研究人员发现，酪氨酸激酶受体2（TRKB，这是一种促进神经元可塑性和抗抑郁反应的脑源性神经营养因子（BDNF）受体）的跨膜结构域具有介导胆固醇突触作用的胆固醇传感功能。然后，研究发现，典型的和速效抗抑郁药都直接与TRKB结合，从而促进TRKB的突触定位及其被BDNF激活。包括原子分子动力学模拟在内的大量计算方法揭示了TRKB二聚体跨膜区的结合位点。TRKB抗抑郁药结合基序的突变会削弱体内和体外对抗抑郁药的细胞、行为和可塑性促进反应。
研究人员认为，与TRKB的结合和BDNF信号的变构促进是抗抑郁作用的常见机制，这可以解释为什么典型的抗抑郁药起效缓慢以及抗抑郁药的分子作用如何能够转化为临床治疗。
据介绍，目前尚不清楚抗抑郁药与其靶标的结合如何产生临床抗抑郁作用。
附：英文原文
Title: Antidepressant drugs act by directly binding to TRKB neurotrophin receptors
Author: Plinio C. Casarotto, Mykhailo Girych, Senem M. Fred, Vera Kovaleva, Rafael Moliner, Giray Enkavi, Caroline Biojone, Cecilia Cannarozzo, Madhusmita Pryiadrashini Sahu, Katja Kaurinkoski, Cecilia A. Brunello, Anna Steinzeig, Frederike Winkel, Sudarshan Patil, Stefan Vestring, Tsvetan Serchov, Cassiano R.A.F. Diniz, Liina Laukkanen, Iseline Cardon, Hanna Antila, Tomasz Rog, Timo Petteri Piepponen, Clive R. Bramham, Claus Normann, Sari E. Lauri, Mart Saarma, Ilpo Vattulainen, Eero Castrén
Issue&Volume: 2021-02-18
Abstract: It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
DOI: 10.1016/j.cell.2021.01.034
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00077-5