Nature Neuroscience 9, 611 - 621 (2006)
Published online: 16 April 2006; | doi:10.1038/nn1680
Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1Isabel Pérez-Otaño1, 2, Rafael Luján3, Steven J Tavalin4, Markus Plomann5, Jan Modregger5, Xiao-Bo Liu6, Edward G Jones6, Stephen F Heinemann7, Donald C Lo1
& Michael D Ehlers1, 81
Department of Neurobiology, Duke University Medical Center, Box 3209, Durham, North Carolina 27710, USA. 2
Cellular Neurobiology Laboratory, Neuroscience Department, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain. 3
Departamento Ciencias Médicas, CRIB-Facultad de Medicina, Universidad de Castilla-La Mancha, 02006 Albacete, Spain. 4
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. 5
Center for Biochemistry and Center for Molecular Medicine, University of Cologne, D-50931 Cologne, Germany. 6
Center for Neuroscience, University of California Davis, Davis, California 95616, USA. 7
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. 8
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Correspondence should be addressed to Isabel Pérez-Otaño otano@unav.es or Michael D Ehlers ehlers@neuro.duke.edu 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.
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