Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals.
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.
Program in Cell and Molecular Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Derek B
DB
Scott
Ioannis
I
Michailidis
Yuanyue
Y
Mu
Diomedes
D
Logothetis
Michael D
MD
Ehlers
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014982:Xenopus laevis
C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D021382:Protein Sorting Signals; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate