Scott Derek B, Michailidis Ioannis, Mu Yuanyue, Logothetis Diomedes, Ehlers Michael D
Program in Cell and Molecular Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Neurosci. 2004 Aug 11;24(32):7096-109. doi: 10.1523/JNEUROSCI.0780-04.2004.
Regulation of the abundance of NMDA receptors (NMDARs) at excitatory synapses is critical during changes in synaptic efficacy underlying learning and memory as well as during synapse formation throughout neural development. However, the molecular signals that govern NMDAR delivery, maintenance, and internalization remain unclear. In this study, we identify a conserved family of membrane-proximal endocytic signals, two within the NMDAR type 1 (NR1) subunit and one within the NR2A and NR2B subunits, necessary and sufficient to drive the internalization of NMDARs. These endocytic motifs reside in the region of NMDAR subunits immediately after the fourth membrane segment, a region implicated in use-dependent rundown and NMDA channel inactivation. Although endocytosis driven by the distal C-terminal domain of NR2B is followed by rapid recycling, internalization mediated by membrane-proximal motifs selectively targets receptors to late endosomes and accelerates degradation. These results define a novel conserved signature of NMDARs regulating internalization and postendocytic trafficking.
在学习和记忆所依赖的突触效能变化过程中，以及在整个神经发育过程中的突触形成期间，兴奋性突触处N-甲基-D-天冬氨酸受体（NMDARs）数量的调节至关重要。然而，控制NMDAR传递、维持和内化的分子信号仍不清楚。在本研究中，我们鉴定出一个保守的膜近端内吞信号家族，其中两个位于NMDAR 1型（NR1）亚基内，一个位于NR2A和NR2B亚基内，它们对于驱动NMDAR的内化是必要且充分的。这些内吞基序位于NMDAR亚基紧接第四膜段之后的区域，该区域与使用依赖性衰减和NMDA通道失活有关。虽然由NR2B的远端C末端结构域驱动的内吞作用之后是快速循环，但由膜近端基序介导的内化作用会选择性地将受体靶向晚期内体并加速降解。这些结果定义了一种调节内化和内吞后运输的NMDARs新的保守特征。
