Subunit-Specific Regulation Of Glutamate Receptors

National Institute Of Neurological Disorders And Stroke

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Abstract

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 trafficking of NMDA receptor subunits, specifically focusing on receptor phosphorylation. We find that the NR2B subunit, and not NR2A, is specifically phosphorylated by casein kinase 2 (CK2) on a critical residue in the NR2B C-terminal domain. CK2 phosphorylation of NR2B increases in the second postnatal week and is important in the subunit switch (NR2B to NR2A), which takes place in many cortical regions during development and in response to activity. These data support unique contributions of the individual NMDA receptor subunits to NMDA receptor trafficking and localization. We are also studying the specific regulation of NR2A and NR2B by the PSD-95 family of proteins. Our results support a unique role for SAP102 in regulating NR2B-containing NMDA receptors. We have also examined the postsynaptic machinery that mediates NMDA receptor exocytosis and identified SNAP-23 as a critical protein regulating glutamate receptor surface expression. In addition to NMDA receptors, we have characterized the trafficking of kainate receptors through the secretory pathway en route to the plasma membrane. We have identified two distinct phosphorylation sites within kainate receptors that regulate intracellular transport and surface expression.