Recent investigations into glutamate receptor function have identified important roles for these receptors in regulating the function of the hippocampus, a primary site of pathology in certain neurological disorders such as Alzheimer's disease and temporal lobe epilepsy. The studies outlined in this proposal will help to elucidate the mechanisms that regulate the function of glutamate receptors and therefore lead to a clearer understanding of hippocampal function. The purpose of these studies is to determine the role that G-protein-coupled receptor kinase 2 (GRK2) plays in regulating the function of metabotropic glutamate receptor 5 (mGluR5). The following specific aims will be tested.
Specific aim 1 is to test the hypothesis that mGluR5 undergoes GRK2-dependent phosphorylation and desensitization. The effect of GRK2 overexpression on mGluR5 coupling to inward-rectifier potassium channels, phosphoinositide hydrolysis, and release of Ca2+ from intracellular stores will be determined. The desensitization of these responses and the phosphorylation of mGluR5 will be monitored.
Specific aim 2 is to identify the specific phosporylation sites on mGluR5 that are responsible for GRK2-mediated desensitization. The desensitization and phosphorylation of mutant mGluR5 in which specific phosphorylation sites have been mutated will be determined.
Specific aim 3 is to determine the effect of GRK2 inhibition on mGluR5 signaling in hippocampal slices. Peptide inhibitors of GRK2 and functional GRK2 antibodies will be applied to hippocampal pyramidal cells through a patch pipette and the desensitization of mGluR5-mediated current recordings upon repeated application of agonist will be monitored.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS011065-01
Application #
6207309
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Talley, Edmund M
Project Start
2000-07-01
Project End
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$30,916
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sorensen, Scott D; Conn, P Jeffrey (2003) G protein-coupled receptor kinases regulate metabotropic glutamate receptor 5 function and expression. Neuropharmacology 44:699-706
Sorensen, Scott D; Nicole, Olivier; Peavy, Richard D et al. (2003) Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol 64:1199-209
Sorensen, Scott D; Macek, Thomas A; Cai, Zhaohui et al. (2002) Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function. Mol Pharmacol 61:1303-12