Inositol 1,4,5-triphosphate receptors and NAD(P)H mediate Ca2+ signaling required for hypoxic preconditioning of hippocampal neurons.
Inositol 1,4,5-triphosphate receptors and NAD(P)H mediate Ca2+ signaling required for hypoxic preconditioning of hippocampal neurons.
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DOI：
10.1016/j.neuroscience.2009.02.013
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发表时间：
2009-04-21
期刊：
影响因子：
3.3
通讯作者：
McKleroy, W.
中科院分区：
文献类型：
--
作者：
Bickler, P. E.;Fahlman, C. S.;Gray, J.;McKleroy, W.
关键词：
神经元暴露于非致死性低氧应激可大大减少随后严重缺血（低氧预处理，HPC）期间的细胞死亡。在大鼠海马的器官型培养中，我们证明HPC需要由细胞质NAD（P）H增加触发的三磷酸肌醇（IP 3）受体依赖性Ca 2+从内质网（ER）释放。用细胞内BAPTA螯合Ca 2+，用毒胡萝卜素消耗ER Ca 2+库，用xestospongin阻断IP 3受体，以及对IP 3受体亚型1的RNA干扰，都减弱了耐受诱导所需的[Ca 2 +]i（50-100 nM）的适度增加。[Ca 2 +]i增加HPC和HPC后的神经保护不能阻止NMDA受体阻滞或从浴介质中除去Ca 2+。在缺氧过程中CA 1神经元中增加的NAD（P）H荧光和证明NADH操纵以IP 3R依赖的方式增加[Ca 2 +]i揭示了细胞氧化还原状态在从ER释放Ca 2+中的主要作用。IP 3受体的阻断和细胞内Ca 2+螯合阻止了已知HPC信号传导靶点的磷酸化，包括MAPK p42/44（ERK）、蛋白激酶B（Akt）和CREB。我们的结论是，内质网，通过氧化还原/NADH依赖的细胞内钙库的释放，是一个重要的调解人的神经保护反应，缺氧应激。
Exposure of neurons to a non-lethal hypoxic stress greatly reduces cell death during subsequent severe ischemia (hypoxic preconditioning, HPC). In organotypic cultures of rat hippocampus, we demonstrate that HPC requires inositol triphosphate (IP3) receptor-dependent Ca2+ release from the endoplasmic reticulum (ER) triggered by increased cytosolic NAD(P)H. Ca2+ chelation with intracellular BAPTA, ER Ca2+ store depletion with thapsigargin, IP3 receptor block with xestospongin, and RNA interference against subtype 1 of the IP3 receptor all blunted the moderate increases in [Ca2+]i (50–100 nM) required for tolerance induction. Increases in [Ca2+]i during HPC and neuroprotection following HPC was not prevented with NMDA receptor block or by removing Ca2+ from the bathing medium. Increased NAD(P)H fluorescence in CA1 neurons during hypoxia and demonstration that NADH manipulation increases [Ca2+]i in an IP3R-dependent manner revealed a primary role of cellular redox state in liberation of Ca2+ from the ER. Blockade of IP3Rs and intracellular Ca2+ chelation prevented phosphorylation of known HPC signaling targets, including MAPK p42/44 (ERK), protein kinase B (Akt) and CREB. We conclude that the endoplasmic reticulum, acting via redox/NADH-dependent intracellular Ca2+ store release, is an important mediator of the neuroprotective response to hypoxic stress.
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影响因子：
3.3
作者：
Bickler, PE;Fahlman, CS
通讯作者：
Fahlman, CS
影响因子：
5.7
作者：
Bickler, Philip E.;Fahlman, Christian S.
通讯作者：
Fahlman, Christian S.
影响因子：
4.7
作者：
Bickler, PE;Fahlman, CS;Ferriero, DM
通讯作者：
Ferriero, DM
DOI：
10.1073/pnas.0702489104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Li, Chi;Wang, Xiaoli;White, Carl
通讯作者：
White, Carl
影响因子：
8.8
作者：
Bickler, PE;Zhan, XH;Fahlman, CS
通讯作者：
Fahlman, CS