The responsiveness of a neuron to neurotransmitter released from a presynaptic cell is determined by the type and amount of receptor expressed on the postsynaptic membrane. The unique distribution of receptors and their subtypes within a single cell and throughout the brain requires highly selective intracellular targeting mechanisms. My laboratory studies the regulation of glutamate receptor trafficking and localization using a combination of biochemical and molecular techniques. We are investigating the differential sorting of NMDA receptor subunits following endocytosis from the plasma membrane. Using both heterologous cells and primary hippocampal cultures, we have examined the fate of internalized receptors. The NR2B subunit, which is highly expressed early in development, is sorted into recycling endosomes; whereas the NR2A subunit, which is highly expressed in adult animals, is sorted into the late endosomal/lysosomal pathway. These data support unique contributions of the individual NMDA receptor subunits to NMDA receptor stabilization at the cell surface and their ability to recycle from endocytic compartments back to the cell surface. In addition, we have identified distinct binding sites within the NR2B C-terminus important for the interaction with the AP-2 adaptor complex and the protein PSD-95. These proteins differentially regulate the density of NMDA receptors on the cell surface. In another project, we are investigating the phosphorylation of metabotropic glutamate receptors. We are identifying the specific residues of mGluR5 that are phosphorylated in vitro and in primary neuronal cultures. These studies will allow us to study the functional consequences of glutamate receptor phosphorylation and the regulation of receptor trafficking and localization. Finally, we have characterized the trafficking of the kainate receptor subunits, GluR6 and KA2, through the secretory pathway en route to the plasma membrane. We are in the process of defining the specific motifs within these receptors that regulate intracellular transport and surface expression.
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