Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac)
Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac)
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DOI：
10.1073/pnas.052712799
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发表时间：
2002-03
影响因子：
11.1
通讯作者：
P. Svenningsson;E. Tzavara;J. Witkin;A. Fienberg;G. Nomikos;P. Greengard
中科院分区：
文献类型：
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作者：
P. Svenningsson;E. Tzavara;J. Witkin;A. Fienberg;G. Nomikos;P. Greengard
氟西汀（百忧解）是治疗抑郁症最广泛使用的药物。然而，除了氟西汀增加突触可用性的血清素这一事实之外，对其临床功效的分子基础知之甚少。在这里，我们表明，在体内，氟西汀无论是急性还是长期给药，都能调节前额皮质、海马和纹状体多个位点的多巴胺和 cAMP 调节的 Mr 32,000 磷蛋白 (DARPP-32) 的磷酸化状态。急性给予氟西汀会增加 DARPP-32 在蛋白激酶 A 位点 Thr-34 和酪蛋白激酶 1 位点 Ser-137 的磷酸化，并降低细胞周期蛋白依赖性激酶 5 位点 Thr-75 的磷酸化。这些变化中的每一个都通过不同的信号传导途径，增强对蛋白磷酸酶-1（大脑中主要的丝氨酸/苏氨酸蛋白磷酸酶）的抑制。 Fluoxetine 还可增加 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体亚基 GluR1 Ser-831 和 Ser-845 的磷酸化。在 DARPP-32 敲除小鼠中，氟西汀介导的 AMPA 受体 Ser-845-GluR1 磷酸化增加以及抗抑郁功效动物试验中对氟西汀的有益反应均大幅降低，表明这种磷蛋白在氟西汀的抗抑郁作用中发挥着关键作用。长期接受氟西汀治疗的小鼠 DARPP-32 mRNA 和蛋白质水平升高，磷酸化 Ser-137–DARPP-32 和磷酸化 Ser-831–GluR1 增加的能力下降。这些慢性变化可能与氟西汀治疗效果延迟起效有关。
Fluoxetine (Prozac) is the most widely prescribed medication for the treatment of depression. Nevertheless, little is known about the molecular basis of its clinical efficacy, apart from the fact that fluoxetine increases the synaptic availability of serotonin. Here we show that, in vivo, fluoxetine, given either acutely or chronically, regulates the phosphorylation state of dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) at multiple sites in prefrontal cortex, hippocampus, and striatum. Acute administration of fluoxetine increases phosphorylation of DARPP-32 at the protein kinase A site, Thr-34, and at the casein kinase-1 site, Ser-137, and decreases phosphorylation at the cyclin-dependent kinase 5 site, Thr-75. Each of these changes contributes, through distinct signaling pathways, to increased inhibition of protein phosphatase-1, a major serine/threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetine-mediated increase in AMPA receptor phosphorylation at Ser-845–GluR1 and the beneficial responsiveness to fluoxetine in an animal test of antidepressant efficacy were strongly reduced in DARPP-32 knockout mice, indicating a critical role for this phosphoprotein in the antidepressant actions of fluoxetine. Mice chronically treated with fluoxetine had increased levels of DARPP-32 mRNA and protein and a decreased ability to increase phospho-Ser-137–DARPP-32 and phospho-Ser-831–GluR1. These chronic changes may be relevant to the delayed onset of therapeutic efficacy of fluoxetine.