NMDA-induced phosphorylation and regulation of mGluR5

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2002-09, Vol.73 (2), p.299-306
• Main Authors: Alagarsamy, Sudar, Rouse, Susan T, Junge, Candace, Hubert, G.W, Gutman, David, Smith, Yoland, Conn, P.Jeffrey
• Format: Article
• Language: English
• Subjects: Animals; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Desensitization; Electrophysiology; Excitatory Amino Acid Agonists - pharmacology; Glutamate; Hydrolysis; In Vitro Techniques; Kinase; LTP; Male; Metabotropic; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Oocytes - drug effects; Patch-Clamp Techniques; Phosphatase; Phosphatidylinositols - metabolism; Phosphorylation; Protein Kinase C - drug effects; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - drug effects; Xenopus laevis
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(02)00826-2

Glutamate regulates neuronal function by acting on ionotropic receptors such as the N-methyl- d-aspartate (NMDA) receptor and metabotropic receptors (mGluRs). We have previously shown that low concentrations of NMDA are able to significantly potentiate mGluR5 responses via activation of a protein phosphatase and reversal of phosphorylation-induced desensitization. While low concentrations of NMDA are able to potentiate mGluR5 responses, higher concentrations of NMDA are actually inhibitory. In this report, we show that NMDA receptors and mGluR5 are highly colocalized in cortical regions. We also show that in voltage-clamp recordings obtained from Xenopus oocytes expressing mGluR5 and NMDA receptors, high concentrations of NMDA (50–100 μM) that elicited large currents (>400 nA) caused an inhibition of mGluR5 currents. Additionally, agonist-induced phosphoinositide hydrolysis presumably mediated by activation of mGluR5, is inhibited by NMDA (30 μM and above). Additional data presented in this report suggest that the inhibitory effect of NMDA is caused by phosphorylation of mGluR5 at protein kinase C (PKC) sites since NMDA induces phosphorylation of the receptor as measured in a back phosphorylation assay.