On page 611 of this issue, Pérez-Otaño and colleagues look into the mechanism by which NR3A-containing NMDA receptors are cleared from synapses in hippocampal cultures. Although it has been reported previously that the NR1 subunit (common to all NMDA receptors) coalesces at emerging synaptic sites in maturing cultures, the authors observed here that the NR3A subunit remained diffusely distributed along the dendritic membrane. Under baseline conditions, NR3A-containing receptors were internalized at much higher rates than receptors lacking NR3A. Inhibitors blocking either neural activity entirely, or NMDA receptor activity specifically, prevented the endocytosis of NR3A complexes.
How are NR3A-containing NMDA receptors targeted for preferential activity-dependent endocytosis? The authors found that the intracellular tail of NR3A, but not of other subunits, interacts with PACSIN1, a neuron-specific multivalent adaptor molecule that had already been implicated in regulation of endocytosis as well as the actin cytoskeleton. PACSIN1 linked NR3A to the clathrin-dependent endocytosis machinery, and expression of a fragment interfering with PACSIN1 inhibited NR3A internalization and increased NR3A localization at bona fide postsynaptic specializations. The figure is an artistic rendition of NR3A (green) 'escaping' the postsynaptic density, presumably aided by PACSIN1.
This is a preview of subscription content, access via your institution
