Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
Antidepressant drugs act by directly binding to TRKB neurotrophin receptors.
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DOI：
10.1016/j.cell.2021.01.034
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发表时间：
2021-03-04
期刊：
影响因子：
64.5
通讯作者：
Castrén E
中科院分区：
文献类型：
--
作者：
Casarotto PC;Girych M;Fred SM;Kovaleva V;Moliner R;Enkavi G;Biojone C;Cannarozzo C;Sahu MP;Kaurinkoski K;Brunello CA;Steinzeig A;Winkel F;Patil S;Vestring S;Serchov T;Diniz CRAF;Laukkanen L;Cardon I;Antila H;Rog T;Piepponen TP;Bramham CR;Normann C;Lauri SE;Saarma M;Vattulainen I;Castrén E
目前尚不清楚抗抑郁药物与其靶点的结合如何产生临床抗抑郁作用。我们发现酪氨酸激酶受体2（TRKB）的跨膜结构域，脑源性神经营养因子（BDNF）受体，促进神经元可塑性和抗抑郁反应，具有胆固醇传感功能，介导的突触效应的胆固醇。然后，我们发现典型的和快速作用的抗抑郁药都直接结合TRKB，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广泛计算方法揭示了TRKB二聚体跨膜区域的结合位点。TRKB抗抑郁剂结合基序的突变损害了体外和体内对抗抑郁剂的细胞、行为和可塑性促进反应。我们认为，结合TRKB和变构促进BDNF信号传导是抗抑郁作用的共同机制，这可能解释了为什么典型的抗抑郁药作用缓慢，以及抗抑郁药的分子效应如何转化为临床情绪恢复。几种抗抑郁药，包括SSRIs和氯胺酮，直接与TRKB结合TRKB在跨膜区二聚化形成氟西汀的结合口袋抗抑郁药与TRKB的结合促进BDNF作用和可塑性TRKB跨膜区的点突变阻断抗抑郁药的作用典型和快速作用的抗抑郁药与BDNF受体TRKB的直接结合解释了抗抑郁药的细胞生物学和行为学作用。这种机制将抗抑郁作用与神经元可塑性直接联系起来，并可以解释典型抗抑郁药的缓慢作用。
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. Several antidepressants, including SSRIs and ketamine, directly bind to TRKB TRKB dimerization at transmembrane region forms a binding pocket for fluoxetine Antidepressant binding to TRKB facilitates BDNF action and plasticity Point mutation in TRKB transmembrane region blocks the effects of antidepressants Direct binding of both typical and fast-acting antidepressants to the BDNF receptor TRKB accounts for cell biological and behavioral actions of antidepressants. This mechanism directly connects antidepressant action to neuronal plasticity and may explain the slow action of typical antidepressants.
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DOI：
10.1083/jcb.150.6.1423
发表时间：
2000-09-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Du J;Feng L;Yang F;Lu B
通讯作者：
Lu B
影响因子：
2.8
作者：
BEUTLER, TC;MARK, AE;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
影响因子：
4.3
作者：
Alford RF;Koehler Leman J;Weitzner BD;Duran AM;Tilley DC;Elazar A;Gray JJ
通讯作者：
Gray JJ
氯胺酮和快速作用的抗抑郁药：介绍新的神经生物学的窗口，用于情绪障碍疗法。
影响因子：
10.5
作者：
Abdallah CG;Sanacora G;Duman RS;Krystal JH
通讯作者：
Krystal JH
DOI：
10.1111/j.1601-183x.2012.00801.x
发表时间：
2012-07
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Andero R;Ressler KJ
通讯作者：
Ressler KJ