In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death.
In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death.
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DOI：
10.1016/j.neuroscience.2008.01.080
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发表时间：
2009-01-12
期刊：
影响因子：
3.3
通讯作者：
Hardingham, G. E.
中科院分区：
文献类型：
--
作者：
Martel, M. -A.;Wyllie, D. J. A.;Hardingham, G. E.
研究表明，与nr2a - NMDA受体相比，含有nr2b的NMDA受体具有促进存活和突触增强的特性，具有选择性地促进死亡前信号传导和突触抑制的倾向。因此，成熟神经元突触中含有nr2a的NMDA受体的优先定位可以解释突触与突触外NMDA受体信号传导的差异。我们研究了NMDA受体是否可以在NR2A显著表达和突触和突触外NMDA受体之间亚单位特异性差异之前，在发育阶段的神经元中介导存活、死亡和突触增强的信号。我们发现，在发育中的海马神经元中，NMDA受体电流对NR2B拮抗剂伊芬普罗地尔的敏感性逐渐降低适用于突触和突触外位置。然而，在突触外电流中，这种减少不那么剧烈，这表明NR2A确实优先而不是完全地分割到DIV bbb12的突触位置。然后，我们研究了DIV10的NMDA受体信号传导，当突触和突触外NMDA受体都以绝大多数和同等程度的nr2b为主时。为了分析促存活信号，我们研究了突触NMDA受体活性对司陶孢素诱导的细胞凋亡的影响。用MK-801或伊芬地尔阻断自发性NMDAR活性加重了凋亡损伤。此外，MK-801和伊芬普罗地尔均通过增强突触活性来拮抗神经保护作用。毒性剂量NMDA诱导的促死亡信号也可被nr2b特异性拮抗剂阻断。使用突触NMDA受体依赖性突触增强的细胞培养模型，我们发现这完全是由含有nr2b的NMDARs介导的，与nr2b特异性拮抗剂和使用选择性和非选择性剂量的nr2a偏好拮抗剂NVP-AAM077有关。因此，在单个神经元内，NR2B-NMDA受体能够介导存活和死亡信号，以及NMDA受体依赖性突触增强模型。在这种情况下，亚基差异不能解释NMDA受体信号传导的二分性。
It has been suggested that NR2B-containing NMDA receptors have a selective tendency to promote pro-death signalling and synaptic depression, compared to the survival promoting, synapse potentiating properties of NR2A-containing NMDA receptors. A preferential localization of NR2A-containing NMDA receptors at the synapse in maturing neurons could thus explain differences in synaptic vs. extrasynaptic NMDA receptor signalling. We have investigated whether NMDA receptors can mediate signalling to survival, death, and synaptic potentiation, in neurons at a developmental stage prior to significant NR2A expression and subunit-specific differences between synaptic and extrasynaptic NMDA receptors. We show that in developing hippocampal neurons, the progressive reduction in sensitivity of NMDA receptor currents to the NR2B antagonist ifenprodil applies to both synaptic and extrasynaptic locations. However, the reduction is less acute in extrasynaptic currents, indicating that NR2A does partition preferentially, but not exclusively, into synaptic locations at DIV>12. We then studied NMDA receptor signalling at DIV10, when both synaptic and extrasynaptic NMDA receptors are both overwhelmingly and equally NR2B-dominated. To analyse pro-survival signalling we studied the influence of synaptic NMDA receptor activity on staurosporine-induced apoptosis. Blockade of spontaneous NMDAR activity with MK-801, or ifenprodil exacerbated the apoptotic insult. Furthermore, MK-801 and ifenprodil both antagonized neuroprotection promoted by enhancing synaptic activity. Pro-death signalling induced by a toxic dose of NMDA is also blocked by NR2B-specific antagonists. Using a cell culture model of synaptic NMDA receptor-dependent synaptic potentiation, we find that this is mediated exclusively by NR2B-containing NMDARs, as implicated by NR2B-specific antagonists and the use of selective vs. non-selective doses of the NR2A-preferring antagonist NVP-AAM077. Therefore, within a single neuron, NR2B-NMDA receptors are able to mediate both survival and death signalling, as well as model of NMDA receptor-dependent synaptic potentiation. In this instance, subunit differences cannot account for the dichotomous nature of NMDA receptor signalling.
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