Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland.
J Cereb Blood Flow Metab. 2011 May;31(5):1196-210. doi: 10.1038/jcbfm.2011.26. Epub 2011 Mar 2.
The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.
Bcl-2 同源（BH）结构域 3 仅蛋白是 Bcl-2 基因家族中的一个促凋亡亚群，通过对线粒体的影响来调节细胞死亡。BH3 仅蛋白对各种细胞应激原作出反应，并通过结合和失活抗凋亡 Bcl-2 家族成员以及直接激活 Bax 等多 BH 结构域促凋亡蛋白来促进细胞死亡。在这里，我们回顾了它们在癫痫持续状态病理生理学中的体内证据，并将其与缺血和创伤性脑损伤进行了对比。啮齿动物的癫痫发作会激活三种有效的促凋亡 BH3 仅蛋白：Bid、Bim 和 Puma。对每种 BH3 仅蛋白缺失的小鼠在癫痫发作后的损伤分析支持 Puma 具有因果作用，在较小程度上支持 Bim，但令人惊讶的是，Bid 没有。在缺血和创伤中，细胞死亡的病理生理学的核心方面重叠，多种 BH3 仅蛋白也被激活，并且已经证明 Bid 是神经元死亡所必需的。这些发现表明，虽然每种神经损伤都会激活多种 BH3 仅蛋白，但它们的功能贡献可能具有特异性。未来的挑战包括评估其余的 BH3 仅蛋白，解释不同的因果贡献，如果可能的话，在缺乏多种 BH3 仅蛋白的小鼠模型中探索神经学结果。
