AMPA受体亚基GluR2的依赖于ADAR2的RNA编辑决定了前脑缺血中神经元的易损性。
ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia.
作者信息
Peng Peter L, Zhong Xiafen, Tu Weihong, Soundarapandian Mangala M, Molner Peter, Zhu Dongya, Lau Lorraine, Liu Shuhong, Liu Fang, Lu Youming
机构信息
Biomolecular Science Center, College of Biomedical Sciences, University of Central Florida, Orlando, Florida 32816, USA.
出版信息
Neuron. 2006 Mar 2;49(5):719-33. doi: 10.1016/j.neuron.2006.01.025.
ADAR2 is a nuclear enzyme essential for GluR2 pre-mRNA editing at Q/R site-607, which gates Ca2+ entry through AMPA receptor channels. Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons. Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult. Generation of a stable ADAR2 gene silencing by delivering small interfering RNA (siRNA) inhibits GluR2 Q/R site editing, leading to degeneration of ischemia-insensitive neurons. Direct introduction of the Q/R site edited GluR2 gene, GluR2(R607), rescues ADAR2 degeneration. Thus, ADAR2-dependent GluR2 Q/R site editing determines vulnerability of neurons in the rat hippocampus to forebrain ischemia.
ADAR2是一种核酶，对于GluR2前体mRNA在Q/R位点607处的编辑至关重要，该位点控制着Ca2+通过AMPA受体通道的进入。在此，我们表明成年大鼠的前脑缺血会选择性降低ADAR2酶的表达，从而破坏易损神经元中GluR2亚基的RNA Q/R位点编辑。通过表达外源性ADAR2b基因或组成型活性CREB（VP16-CREB，可诱导内源性ADAR2的表达）来恢复GluR2 Q/R位点编辑，可保护大鼠海马体中的易损神经元免受前脑缺血损伤。通过递送小干扰RNA（siRNA）产生稳定的ADAR2基因沉默会抑制GluR2 Q/R位点编辑，导致对缺血不敏感的神经元退化。直接导入经Q/R位点编辑的GluR2基因GluR2(R607)可挽救ADAR2退化。因此，ADAR2依赖的GluR2 Q/R位点编辑决定了大鼠海马体中神经元对前脑缺血的易损性。
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