Spadin，一种分拣蛋白衍生肽，靶向啮齿动物 TREK-1 通道：抗抑郁药物设计中的新概念。,PLOS Biology

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Spadin，一种分拣蛋白衍生肽，靶向啮齿动物 TREK-1 通道：抗抑郁药物设计中的新概念。
PLOS Biology ( IF 7.8 ) Pub Date : 2010-04-13 , DOI: 10.1371/journal.pbio.1000355
Jean Mazella ₁ , Olivier Pétrault , Guillaume Lucas , Emmanuel Deval , Sophie Béraud-Dufour , Carine Gandin , Malika El-Yacoubi , Catherine Widmann , Alice Guyon , Eric Chevet , Said Taouji , Grégory Conductier , Alain Corinus , Thierry Coppola , Gabriella Gobbi , Jean-Louis Nahon , Catherine Heurteaux , Marc Borsotto

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目前的抗抑郁治疗对许多人来说是不够的，当它们有效时，需要几周的给药才能观察到治疗效果。改善抑郁症的治疗具有挑战性。最近，双孔域钾通道 TREK-1 已被确定为抑郁症的新靶点，其拮抗剂可能成为有效的抗抑郁药。在小鼠中，TREK-1 基因的缺失导致模拟抗抑郁治疗的抗抑郁表型。在这里，我们在小鼠中验证了 spadin 的抗抑郁作用，这是一种分泌肽，来源于神经降压素受体 3 (NTSR3/Sortilin) 成熟产生的前肽，并通过 TREK-1 抑制起作用。NTSR3/Sortilin 与 TREK-1 通道交互，如来自共表达两种蛋白质的 COS-7 细胞和皮质神经元的 TREK-1 和 NTSR3/Sortilin 的免疫沉淀所示。TREK-1 和 NTSR3/Sortilin 共定位于小鼠皮层神经元中。Spadin 以 10 nM 的亲和力与 TREK-1 特异性结合。电生理学研究表明，spadin 可有效阻断脑切片中 COS-7 细胞、培养的海马锥体神经元和 CA3 海马神经元中的 TREK-1 活性。Spadin 还在体内诱导中缝背核中 5-HT 神经元放电率的增加。在预测抗抑郁反应的五项行为测试中，spadin 治疗的小鼠表现出对抑郁症的抵抗力，正如在 TREK-1 缺陷小鼠中发现的那样。更重要的是，用 spadin 静脉注射 4 天治疗不仅诱导了强烈的抗抑郁作用，而且还增强了 CREB 蛋白的海马磷酸化和神经发生，这被认为是选择性 5-羟色胺再摄取抑制剂长期治疗后抗抑郁作用的关键标志物。这项工作还显示了使用 AlphaScreen 技术开发了一种可靠的方法来定量小鼠血清中的前肽。这些发现指出，spadin 是一种推定的新一代抗抑郁药，起效迅速。Spadin 可被视为第一个被鉴定的天然抗抑郁肽。它对应于解决抑郁症治疗的新概念。这项工作还显示了使用 AlphaScreen 技术开发了一种可靠的方法来定量小鼠血清中的前肽。这些发现指出，spadin 是一种推定的新一代抗抑郁药，起效迅速。Spadin 可被视为第一个被鉴定的天然抗抑郁肽。它对应于解决抑郁症治疗的新概念。这项工作还显示了使用 AlphaScreen 技术开发了一种可靠的方法来定量小鼠血清中的前肽。这些发现指出，spadin 是一种推定的新一代抗抑郁药，起效迅速。Spadin 可被视为第一个被鉴定的天然抗抑郁肽。它对应于解决抑郁症治疗的新概念。

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Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.

更新日期：2019-11-01

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