An activity-dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors
An activity-dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors
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DOI：
10.1046/j.0953-816x.2001.01541.x
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发表时间：
2001-04-01
影响因子：
3.4
通讯作者：
Nicoletti, F
中科院分区：
文献类型：
--
作者：
Bruno, V;Battaglia, G;Nicoletti, F
已知 I 类代谢型谷氨酸受体（mGlu(1) 或 -(5) 受体）的激活可增强或减弱兴奋毒性神经元死亡，具体取决于实验条件。我们研究了这些受体在调节兴奋性毒性方面可能在两种不同功能模式之间切换的可能性。在皮层细胞的混合培养物中，选择性 mGlu(1/5) 激动剂 3,5-二羟基苯基甘氨酸 (DHPG) 会放大由 NMDA 毒性脉冲诱导的神经变性。当 DHPG 与 NMDA 组合或在 NMDA 脉冲之前短暂应用于培养物时，观察到了这种效应。然而，连续两次使用 DHPG 始终能产生神经保护作用。在几乎不含星形胶质细胞的皮层神经元纯培养物中，使用 DHPG 或使君子酸（mGlu(1/5) 受体的有效激动剂）观察到类似的效果。然而，在海马锥体神经元的培养物中，仅观察到 DHPG 的保护作用，这表明在这些特定的培养物中，I 组 mGlu 受体内源性地转变为“神经保护模式”。在皮层细胞的混合培养物中检查了从促进到抑制的活动依赖性转换的特征。当两次用药间隔1-45分钟时，观察到对DHPG反应的转变，但当间隔延长至90分钟时，这种转变消失。此外，这种现象需要 mGlu(5) 受体的初始激活（如使用亚型选择性拮抗剂所示），并由蛋白激酶 C 的激活介导。我们得出结论，I 组 mGlu 受体在调节兴奋性毒性神经元死亡方面受到活性依赖性开关的影响，因此，这些受体的近期“历史”对于激动剂或拮抗剂的反应至关重要。
Activation of group I metabotropic glutamate receptors (mGlu(1) or -(5) receptors) is known to either enhance or attenuate excitotoxic neuronal death depending on the experimental conditions. We have examined the possibility that these receptors may switch between two different functional modes in regulating excitotoxicity. In mixed cultures of cortical cells, the selective mGlu(1/5) agonist, 3,5-dihydroxyphenylglycine (DHPG), amplified neurodegeneration induced by a toxic pulse of NMDA. This effect was observed when DHPG was either combined with NMDA or transiently applied to the cultures prior to the NMDA pulse. However, two consecutive applications of DHPG consistently produced neuroprotection. Similar effects were observed with DHPG or quisqualate (a potent agonist of mGlu(1/5) receptors) in pure cultures of cortical neurons virtually devoid of astrocytes. In cultures of hippocampal pyramidal neurons, however, only protective effects of DHPG were seen suggesting that, in these particular cultures, group I mGlu receptors were endogenously switched into a 'neuroprotective mode'. The characteristics of the activity-dependent switch from facilitation to inhibition were examined in mixed cultures of cortical cells. The switch in the response to DHPG was observed when the two applications of the drug were separated by an interval ranging from 1-45 min, but was lost when the interval was extended to 90 min. In addition, this phenomenon required the initial activation of mGlu(5) receptors (as indicated by the use of subtype-selective antagonists) and was mediated by the activation of protein kinase C. We conclude that group I mGlu receptors are subjected to an activity-dependent switch in regulating excitotoxic neuronal death and, therefore, the recent 'history' of these receptors is critical for the response to agonists or antagonists.