Mutation in the TRKB Cholesterol Recognition Site that blocks Antidepressant Binding does not Influence the Basal or BDNF-Stimulated Activation of TRKB

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Caroline Biojone, Cecilia Cannarozzo, Nina Seiffert, Cassiano R. A. F. Diniz, Cecilia A. Brunello, Eero Castrén, Plinio Casarotto
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引用次数: 0

Abstract

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressant drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Tyr433Phe). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Tyr433Phe mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Tyr433Phe mutant mice (hTRKB.Tyr433Phe) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Tyr433Phe mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task, or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Tyr433Phe mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Tyr433Phe mutants, making them an interesting mouse model for antidepressant research.

Abstract Image

阻断抗抑郁药结合的 TRKB 胆固醇识别位点突变不会影响 TRKB 的基础或 BDNF 刺激激活
脑源性神经营养因子(BDNF)作用于其受体神经营养酪氨酸激酶受体 2(NTRK2,TRKB),在突触功能的发育和维持以及活动或药物诱导的可塑性中发挥着核心作用。TRKB 具有一个倒置的胆固醇识别和排列共识序列(CARC),表明该受体可作为胆固醇传感器。我们最近的研究表明,抗抑郁药物可直接与 TRKB 二聚体的 CARC 结构域结合,而 TRKB CARC 基因突变(Tyr433Phe)后,这种结合以及对抗抑郁药物的生化和行为反应都会消失。然而,尚不清楚这种突变是否也会损害受体功能并导致行为改变。在这里,我们观察到 Tyr433Phe 突变不会改变 BDNF 与 TRKB 的结合,也不会改变 BDNF 诱导的 TRKB 二聚化。在这一系中,杂合Tyr433Phe突变小鼠(hTRKB.Tyr433Phe)胚胎的原代培养物对BDNF诱导的TRKB激活有反应,成年小鼠的样本与野生型同窝小鼠(TRKB.wt)相比,在TRKB激活方面没有任何差异。hTRKB.Tyr433Phe小鼠在诱导恐惧条件反射、情境辨别任务或高架加迷宫中的行为表型与野生型小鼠无异,而杂合BDNF无效等位基因的小鼠在情境辨别任务中表现出表型。综上所述,我们的研究结果表明,TRKB CARC基序中的Tyr433Phe突变并不表现出BDNF反应功能缺失的迹象,而Tyr433Phe突变体中抗抑郁药物与TRKB的结合以及对抗抑郁药物的反应都会丧失,因此它们是一种有趣的抗抑郁药物研究小鼠模型。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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