NMDA RECEPTOR MODIFICATION IN THE FETAL GUINEA-PIG BRAIN DURING HYPOXIA
NMDA RECEPTOR MODIFICATION IN THE FETAL GUINEA-PIG BRAIN DURING HYPOXIA
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DOI：
10.1007/bf00968402
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发表时间：
1992-12-01
影响因子：
4.4
通讯作者：
DELIVORIAPAPADOPOULOS, M
中科院分区：
文献类型：
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作者：
MISHRA, OP;DELIVORIAPAPADOPOULOS, M
研究了母体缺氧对胎儿细胞膜n -甲基- d -天冬氨酸（NMDA）受体及其调控位点修饰的影响。实验在妊娠60天的豚鼠身上进行。豚鼠胎儿暴露于母体缺氧（FiO2 = 7%） 60分钟。胎儿脑组织缺氧的生化记录是ATP和磷酸肌酸水平下降（分别比正常缺氧低91.3%和88.6%）。以MK-801结合特性（Bmax =受体数量，Kd =受体亲和力）作为NMDA受体修饰的指标。从常氧和缺氧胎脑皮层制备P2膜组分，并彻底清洗后进行结合实验。低氧脑组织Bmax从正常氧对照水平0.79 +/- 0.03 pmol/mg蛋白降低至0.58 +/- 0.03 pmol/mg蛋白（P < 0.005）， Kd值从8.54 +/- 0.27 nM降低至4.01 +/- 0.23 nM （P < 0.005）。缺乏谷氨酸和甘氨酸的缺氧脑中MK-801的结合比对照组高100%，表明NMDA受体对激活的敏感性增加。精胺依赖的NMDA受体的最大激活在缺氧动物中增加到44%，而在对照组中为25%。NMDA受体的Mg2+反应不受缺氧影响。缺氧时NMDA受体的亲和力和基础激活（张力）的增加，以及精胺对其激活的增加，会过度刺激NMDA受体-离子通道复合物功能，从而增加胎儿大脑对缺氧的易感性。本研究结果表明，缺氧导致NMDA受体离子通道复合物特定位点（识别、共激活和调节）的差异和选择性修饰。缺氧诱导的NMDA受体调节位点的改变似乎是神经兴奋性毒性的潜在机制。
The effect of maternal hypoxia on the modification of the fetal brain cell membrane N-methyl-D-aspartate (NMDA) receptor and its modulatory sites was investigated. Experiments were conducted in pregnant guinea pigs of 60 days of gestation. Guinea pig fetuses were exposed to maternal hypoxia (FiO2 = 7%) for 60 minutes. Tissue hypoxia in the fetal brain was documented biochemically by decreased levels of ATP and phosphocreatine (91.3% and 88.6% lower than normoxia, respectively). MK-801 binding characteristics (Bmax = number of receptors, Kd = affinity of receptor) were used as an index of NMDA receptor modification. P2 membrane fraction was prepared from the cortex of normoxic and hypoxic fetal brain and washed thoroughly before carrying out the binding assay. In hypoxic brains, Bmax decreased from the normoxic control level 0.79 +/- 0.03 pmol/mg protein to 0.58 +/- 0.03 pmol/mg protein (P < 0.005) and Kd value decreased (increased affinity) from 8.54 +/- 0.27 nM to 4.01 +/- 0.23 nM (P < 0.005) respectively. The MK-801 binding in the absence of added glutamate and glycine in hypoxic brain was 100% higher as compared to controls, indicating an increased sensitivity of the NMDA receptor to activation. The spermine dependent maximum activation of the NMDA receptor increased to 44% in the hypoxic animals as compared to 25% in controls. The Mg2+ response of the NMDA receptor was not affected by hypoxia. The increased affinity and increased basal activation (tone) of the NMDA receptor during hypoxia, as well as its increased activation by spermine, would hyperstimulate the NMDA receptor-ion channel complex function which could increase the susceptibility of the fetal brain to hypoxia. The results of this study indicate that hypoxia causes differential and selective modification of specific sites (recognition, co-activator, and modulatory) of the NMDA receptor ion channel complex. The hypoxia-induced modification of the NMDA receptor modulatory sites appears to be the potential mechanism of neuroexcitotoxicity.