Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity.
Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity.
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阿米替林是一种 TrkA 和 TrkB 受体激动剂，可促进 TrkA/TrkB 异二聚化并具有有效的神经营养活性。
DOI：
10.1016/j.chembiol.2009.05.010
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发表时间：
2009-06-26
影响因子：
--
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Jang SW;Liu X;Chan CB;Weinshenker D;Hall RA;Xiao G;Ye K
神经营养素是Trk受体的同源配体，是同源二聚体，通过对称的二价机制诱导Trk的二聚化。我们报道了抗抑郁药物阿米替林直接与TrkA和TrkB结合，并触发它们的二聚化和激活。阿米替林，但不是任何其他三环或SSRI抗抑郁药，促进初级神经元中TrkA的自动磷酸化，并诱导PC12细胞中的轴突生长。阿米替林结合TrkA和TrkB的胞外区，促进TrkA-TrkB受体的异源二聚化。截断TrkA上的阿米替林结合基序可以取消阿米替林对受体的二聚化作用。给小鼠服用阿米替林可以激活这两种受体，并显著减少红藻氨酸引发的神经细胞死亡。抑制TrkA，而不是TrkB，可以取消阿米替林的神经保护作用，而不会削弱其抗抑郁活性。因此，阿米替林作为TrkA和TrkB的激动剂，具有显著的神经营养活性。
Neurotrophins, the cognate ligands for the Trk receptors, are homodimers and induce Trk dimerization through a symmetric bivalent mechanism. We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or SSRI antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and significantly reduces kainic acid-triggered neuronal cell death. Inhibition of TrkA, but not TrkB, abolishes amitriptyline's neuroprotective effect without impairing its antidepressant activity. Thus, amitriptyline acts as a TrkA and TrkB agonist, and possesses marked neurotrophic activity.
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DOI：
10.1073/pnas.0709102105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Jeanneteau, Freddy;Garabedian, Michael J.;Chao, Moses V.
通讯作者：
Chao, Moses V.
影响因子：
2.9
作者：
Kume, T;Nishikawa, H;Shimohama, S
通讯作者：
Shimohama, S
影响因子：
4.8
作者：
O'Leary, PD;Hughes, RA
通讯作者：
Hughes, RA
影响因子：
4.2
作者：
Culmsee, C;Semkova, I;Krieglstein, J
通讯作者：
Krieglstein, J
影响因子：
10.6
作者：
Caldarone, BJ;Harrist, A;Picciotto, MR
通讯作者：
Picciotto, MR