The Ins and Outs of NMDA Receptors

Although the trafficking of AMPA receptors has received much recent fanfare as a mechanism for synaptic plasticity, NMDA receptors have received less attention in this regard. However, Scott et al. now show that independent regions within the cytoplasmic domains of NMDA receptor type 1 (NR1) and NMDA receptor type 2 (NR2) subunits target NMDA receptors for internalization. Interestingly, the receptors can be sentenced differentially to separate fates, either receptor cycling back to the plasma membrane or degradation. In the NR1 subunit, two independent motifs, one tyrosine-based and one lysine-based, were necessary and sufficient for endocytosis. A similar domain was identified in the NR2A subunit. These internalization sequences, found in the membraneproximal C0 domain of the C terminus, directed the receptors to late endosomes for speedy degradation. In contrast, the NR2B subunit contains a distal C-terminal domain that caused rapid recycling of receptors back to the plasma membrane. These alternative pathways provide flexible signals to control surface expression of NMDA receptors.