ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia
ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia
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DOI：
10.1196/annals.1387.050
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Di Renzo, G. E.
中科院分区：
文献类型：
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作者：
Annunziato, L.;Pignataro, G.;Di Renzo, G. E.
近几年来，虽然钠钙交换体（NCX）在局灶性脑缺血中的相关作用得到了广泛的研究，但对其作用的深入了解仍存在争议。我们探讨了传统的药理学方法，与合成的抑制肽，XIP，或与永久性闭塞大脑中动脉（pMCAO）大鼠脑损伤的程度上的反义策略的药理学抑制这种反向转运蛋白的后果。总的来说，这些研究的结果表明，ncx1和ncx3基因可能在限制缺血性损伤的严重程度方面发挥重要作用，因为它们可能起到抑制[Na+]（i）和[Ca2+]（i）过载的作用。这种机制似乎在缺血性脑中被正常激活，因为我们发现在缺血性损伤后存活的脑区域中，NCX1和NCX3 mRNA水平选择性上调。尽管这种转录增加，NCX1，NCX2和NCX3蛋白质在同侧大脑半球进行广泛的蛋白水解降解。总之，这些结果表明，以增加NCX功能和表达为中心的救援计划可以阻止缺血性损伤的进展。基于这些证据，我们将注意力转向了对NCX上调的转导和转录途径的理解。为了这个目的，我们正在研究是否大脑亚型的Akt，Akt1，这是一个下游效应的神经营养因子，如神经生长因子，可以，除了影响其他促生存级联反应，也发挥其神经保护作用，通过调节ncx1，ncx2和ncx3基因产物的表达和活性。
Over the last few years, although extensive studies have focused on the relevant function played by, the sodium-calcium exchanger (NCX) during focal ischemia, a thorough understanding of its role still remains a controversial issue. We explored the consequences of the pharmacological inhibition of this antiporter with conventional pharmacological approach, with the synthetic inhibitory peptide, XIP, or with an antisense strategy on the extent of brain damage induced by the permanent occlusion of middle cerebral artery (pMCAO) in rats. Collectively, the results of these studies suggest that ncx1 and ncx3 genes could be play a major role to limit the severity of ischemic damage probably as they act to dampen [Na+](i) and [Ca2+](i) overload. This mechanism seems to be normally activated in the ischemic brain as we found a selective upregulation of NCX1 and NCX3 mRNA levels in regions of the brain surviving to an ischemic insult. Despite this transcript increase, NCX1, NCX2, and NCX3 proteins undergo an extensive proteolytic degradation in the ipsilateral cerebral hemisphere. All together these results suggest that a rescue program centered on an increase NCX function and expression could halt the progression of the ischemic damage. On the basis of this evidence we directed our attention to the understanding of the transductional and transcriptional pathways responsible for NCX upregulation. To this aim, we are studying whether the brain isoform of Akt, Akt1, which is a downstream effector of neurotrophic factors, such as NGF can, in addition to affecting the other prosurvival cascades, also exert its neuroprotective effect by modulating the expression and activity of ncx1, ncx2, and ncx3 gene products.