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 have identified several specific residues within mGluR5 that are phosphorylated by protein kinase C. One phosphorylation site determines the regulation of intracellular calcium oscillations in response to mGluR5 activation. These studies will allow us to study the functional consequences of glutamate receptor phosphorylation and the regulation of intracellular signaling and receptor trafficking. Finally, we have characterized the trafficking of the kainate receptor subunit KA2 through the secretory pathway en route to the plasma membrane. We have identified a novel ER-retention motif encoded within the protein that regulates intracellular transport and surface expression.
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