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. In the past year, we have investigated the differential sorting of NMDA receptor subunits following endocytosis from the plasma membrane. Using both heterologous cells and primary hippocampal cultures, we 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. Our initial findings 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 a separate project, we have investigated the phosphorylation of the metabotropic glutamate receptor mGluR5 by a variety of protein kinases in vitro. We are identifying the specific residues that are phosphorylated, and we will soon begin comparing these results to the phosphorylation of mGluR5 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002994-01
Application #
6664236
Study Section
(RBU)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Chen, Bo-Shiun; Roche, Katherine W (2007) Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53:362-8
Pelkey, Kenneth A; Yuan, Xiaoqing; Lavezzari, Gabriela et al. (2007) mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 52:108-17
Lavezzari, Gabriela; Roche, Katherine W (2007) Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent. Neuropharmacology 52:100-7
Chen, Bo-Shiun; Braud, Stephanie; Badger 2nd, John D et al. (2006) Regulation of NR1/NR2C N-methyl-D-aspartate (NMDA) receptors by phosphorylation. J Biol Chem 281:16583-90
Nasu-Nishimura, Yukiko; Hurtado, David; Braud, Stephanie et al. (2006) Identification of an endoplasmic reticulum-retention motif in an intracellular loop of the kainate receptor subunit KA2. J Neurosci 26:7014-21
Kim, Chul Hoon; Braud, Stephanie; Isaac, John T R et al. (2005) Protein kinase C phosphorylation of the metabotropic glutamate receptor mGluR5 on Serine 839 regulates Ca2+ oscillations. J Biol Chem 280:25409-15
Stadtman, Earl R; Arai, Hirofumi; Berlett, Barbara S (2005) Protein oxidation by the cytochrome P450 mixed-function oxidation system. Biochem Biophys Res Commun 338:432-6
Nagappan, Guhan; Lu, Bai (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28:464-71
Pelkey, Kenneth A; Lavezzari, Gabriela; Racca, Claudia et al. (2005) mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 46:89-102
Roche, Katherine W (2004) The expanding role of PSD-95: a new link to addiction. Trends Neurosci 27:699-700

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