Pérez-Otaño Isabel, Luján Rafael, Tavalin Steven J, Plomann Markus, Modregger Jan, Liu Xiao-Bo, Jones Edward G, Heinemann Stephen F, Lo Donald C, Ehlers Michael D
Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, North Carolina 27710, USA.
Nat Neurosci. 2006 May;9(5):611-21. doi: 10.1038/nn1680. Epub 2006 Apr 16.
A key step in glutamatergic synapse maturation is the replacement of developmentally expressed N-methyl-D-aspartate receptors (NMDARs) with mature forms that differ in subunit composition, electrophysiological properties and propensity to elicit synaptic plasticity. However, the mechanisms underlying the removal and replacement of synaptic NMDARs are poorly understood. Here we demonstrate that NMDARs containing the developmentally regulated NR3A subunit undergo rapid endocytosis from the dendritic plasma membrane in cultured rat hippocampal neurons. This endocytic removal is regulated by PACSIN1/syndapin1, which directly and selectively binds the carboxy-terminal domain of NR3A through its NPF motifs and assembles a complex of proteins including dynamin and clathrin. Endocytosis of NR3A by PACSIN1 is activity dependent, and disruption of PACSIN1 function causes NR3A accumulation at synaptic sites. Our results reveal a new activity-dependent mechanism involved in the regulation of NMDAR expression at synapses during development, and identify a brain-specific endocytic adaptor that confers spatiotemporal and subunit specificity to NMDAR endocytosis.
谷氨酸能突触成熟的一个关键步骤是，用亚基组成、电生理特性和引发突触可塑性倾向不同的成熟形式，替换发育过程中表达的N-甲基-D-天冬氨酸受体（NMDARs）。然而，突触NMDARs的去除和替换背后的机制仍知之甚少。在这里，我们证明，含有发育调控的NR3A亚基的NMDARs在培养的大鼠海马神经元中从树突质膜快速内吞。这种内吞去除由PACSIN1/突触结合蛋白1调控，它通过其NPF基序直接且选择性地结合NR3A的羧基末端结构域，并组装包括发动蛋白和网格蛋白在内的蛋白质复合物。PACSIN1介导的NR3A内吞是活性依赖的，PACSIN1功能的破坏会导致NR3A在突触部位积累。我们的结果揭示了一种新的活性依赖机制，参与发育过程中突触处NMDAR表达的调控，并鉴定出一种脑特异性内吞衔接蛋白，它赋予NMDAR内吞时空和亚基特异性。
