Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2011 Apr 6;31(14):5353-64. doi: 10.1523/JNEUROSCI.0282-11.2011.
Dynamic regulation of the localization and function of NMDA receptors (NMDARs) is critical for synaptic development and function. The composition and localization of NMDAR subunits at synapses are tightly regulated and can influence the ability of individual synapses to undergo long-lasting changes in response to stimuli. Here, we examine mechanisms by which EphB2, a receptor tyrosine kinase that binds and phosphorylates NMDARs, controls NMDAR subunit localization and function at synapses. We find that, in mature neurons, EphB2 expression levels regulate the amount of NMDARs at synapses, and EphB activation decreases Ca(2+)-dependent desensitization of NR2B-containing NMDARs. EphBs are required for enhanced localization of NR2B-containing NMDARs at synapses of mature neurons; triple EphB knock-out mice lacking EphB1-3 exhibit homeostatic upregulation of NMDAR surface expression and loss of proper targeting to synaptic sites. These findings demonstrate that, in the mature nervous system, EphBs are key regulators of the synaptic localization of NMDARs.
NMDA 受体（NMDARs）的定位和功能的动态调节对于突触的发育和功能至关重要。突触处 NMDAR 亚基的组成和定位受到严格调控，可影响单个突触对刺激产生持久变化的能力。在这里，我们研究了 EphB2（一种与 NMDAR 结合并使其磷酸化的受体酪氨酸激酶）控制突触处 NMDAR 亚基定位和功能的机制。我们发现，在成熟神经元中，EphB2 的表达水平调节突触处 NMDAR 的数量，EphB 的激活可降低包含 NR2B 的 NMDAR 的 Ca(2+)依赖性脱敏。EphB 对于成熟神经元突触处包含 NR2B 的 NMDAR 的增强定位是必需的；三重 EphB 敲除小鼠（缺乏 EphB1-3）表现出 NMDAR 表面表达的同源性上调和对突触部位的靶向丧失。这些发现表明，在成熟的神经系统中，EphB 是 NMDAR 突触定位的关键调节因子。
