Noradrenergic antidepressant responses to desipramine in vivo are reciprocally regulated by arrestin3 and spinophilin.
Noradrenergic antidepressant responses to desipramine in vivo are reciprocally regulated by arrestin3 and spinophilin.
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DOI：
10.1016/j.neuropharm.2012.02.011
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发表时间：
2012-06
影响因子：
4.7
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Cottingham C;Li X;Wang Q
许多抗抑郁药物，包括三环抗抑郁药地昔帕明(DMI)，被广泛理解为通过调节中枢去甲肾上腺素能神经传递发挥作用。α-2肾上腺素能受体(α-2AR)是去甲肾上腺素能系统的关键调节因子，已有研究表明α-2AR参与了啮齿动物强迫游泳实验中DMI的抗抑郁作用。然而，对抗抑郁药物作用的细胞内调节因子知之甚少。α-2AR的功能受其细胞内相互作用伙伴Arrestin和树突状蛋白SPIN的严格调控。我们以前已经在经典的激动剂效应的背景下建立了α2AR上这些相互作用的蛋白质的竞争和互惠性质，并已经证明DMI是受体上的一个直接的芳香素偏向配体。在目前的研究中，我们报告了α2AAR亚型缺陷的小鼠在前额叶缺乏双MI诱导的抗抑郁行为效应。此外，与野生型对照相比，抑制蛋白3基因缺失的小鼠缺乏抗抑郁反应，而亲刺蛋白缺失的小鼠增强了对双MI的抗抑郁反应，这表明这种由α2AAR介导的反应受到Arrestin和Spinophlin的相互调节。经典的α2AAR激动剂可乐定具有抗抑郁作用，而非三环去甲肾上腺素再摄取抑制剂瑞波西汀则无此作用，支持α通过直接与α2AAR和抑制素3结合而发挥抗抑郁作用的模型。我们的研究结果表明，去甲肾上腺素能抗抑郁药DMI的药理作用与α2AAR的调节有关，并提示操纵这种受体调节模式可能是一种新的、可行的治疗策略。
Many antidepressant drugs, including the tricyclic antidepressant desipramine (DMI), are broadly understood to function by modulating central noradrenergic neurotransmission. α2 adrenergic receptors (α2ARs) are key regulators of the noradrenergic system, and previous work has implicated α2ARs in mediating the antidepressant activity of DMI in the rodent forced swim test (FST). However, little is known about intracellular regulators of antidepressant drug action. α2AR function is tightly regulated by its intracellular interacting partners arrestin and the dendritic protein spinophilin. We have previously established the competitive and reciprocal nature of these interacting proteins at the α2AR in the context of classic agonist effects, and have shown DMI to be a direct arrestin-biased ligand at the receptor. In the present study, we report that mice deficient in the α2AAR subtype lack DMI-induced antidepressant behavioral effects in the FST. As well, mice deficient in arrestin3 lack antidepressant response to DMI, while spinophilin-null mice have enhanced antidepressant response to DMI compared with wild-type controls, indicating that this α2AAR-mediated response is reciprocally regulated by arrestin and spinophilin. The characteristic of α2AAR-dependence and arrestin3 involvement was shared by the antidepressant effect of the classic α2AR agonist clonidine but not the non-tricyclic norepinephrine reuptake inhibitor reboxetine, supporting a model whereby DMI exerts its antidepressant effect through direct engagement of the α2AAR and arrestin3. Our results implicate arrestin- and spinophilin-mediated regulation of the α2AAR in the pharmacology of the noradrenergic antidepressant DMI, and suggest that manipulation of this mode of receptor regulation may represent a novel and viable therapeutic strategy.
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影响因子：
3.6
作者：
Gilsbach, Ralf;Roeser, Christoph;Hein, Lutz
通讯作者：
Hein, Lutz
影响因子：
10.6
作者：
Polter A;Yang S;Zmijewska AA;van Groen T;Paik JH;Depinho RA;Peng SL;Jope RS;Li X
通讯作者：
Li X
影响因子：
64.8
作者：
Hein, L;Altman, JD;Kobilka, BK
通讯作者：
Kobilka, BK
DOI：
10.1073/pnas.97.16.9287
发表时间：
2000-08-01
影响因子：
11.1
作者：
Feng, J;Yan, Z;Greengard, P
通讯作者：
Greengard, P
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT