Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities
Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities
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DOI：
10.1006/bbrc.1999.1683
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发表时间：
1999-11-19
影响因子：
3.1
通讯作者：
Herbert, JM
中科院分区：
文献类型：
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作者：
Bono, F;Lamarche, I;Herbert, JM
外周苯二氮卓受体 (PBR) 与多种线粒体功能有关，但该受体的确切生理作用仍存在争议。由于线粒体在细胞死亡中起核心作用，我们确定了各种 PER 激动剂和拮抗剂对人淋巴母细胞系 U937 细胞凋亡的影响。对于这种细胞类型，发现 PER 激动剂 Ro5-4864 可以强烈保护细胞免受 TNF α 诱导的细胞凋亡。 PER 激动剂的抗凋亡作用是由于与 PER 的选择性相互作用，如下所示：(1) 各种 PER 激动剂的抗凋亡活性与其各自对相同细胞上测定的 PER 的亲和力之间存在密切相关，(2) 中枢苯二氮卓受体激动剂（如氯硝西泮）对细胞存活没有影响，(3) Ro5-4864 对野生型 Jurkat 缺乏抗凋亡活性细胞（缺乏PER受体）以及这种作用在PBR转染的Jurkat细胞上的再现，以及（4）选择性PER拮抗剂对PER激动剂的抗凋亡作用的阻断。因此，本结果表明PER激动剂是有效的抗凋亡化合物，并表明这种作用可能代表了这种神秘受体的主要功能。 (C) 1999 年学术出版社。
The peripheral benzodiazepine receptor (PBR) has been implicated in several mitochondrial functions but the exact physiological role of this receptor is still under debate, Since the mitochondria have been attributed a central role in cell death, we have determined the effects of various PER agonists and antagonists on the apoptosis of the human lymphoblastoid cell line U937. On this cell type, the PER agonist Ro5-4864 was found to strongly protect the cells against apoptosis induced by TNF alpha. The antiapoptotic effect of PER agonists was due to a selective interaction with the PER as demonstrated by: (1) a close correlation between the antiapoptotic activity of various PER agonists and their respective affinity for the PER determined on the same cells, (2) a lack of effect of central benzodiazepine receptors agonists such as clonazepam on cell survival, (3) the lack of an antiapoptotic activity of Ro5-4864 on wild-type Jurkat cells (lacking the PER receptor) and the reappearance of this effect on PBR-transfected Jurkat cells, and (4) the blockade of the antiapoptotic effect of PER agonists by a selective PER antagonist, The present results therefore indicate that PER agonists are potent antiapoptotic compounds and show that this effect might represent a major function for this enigmatic receptor. (C) 1999 Academic Press.