NMDA-induced phosphorylation and regulation of mGluR5.
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 microM) 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 microM 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.
Alagarsamy
Sudar
S
Ferring Research Institute Inc., 3550 General Atomics Court, Building 2, Room 443, San Diego, CA 92121, USA. sudarkody.alagarsamy@ferring.com
Rouse
Susan T
ST
Junge
Candace
C
Hubert
G W
GW
Gutman
David
D
Smith
Yoland
Y
Conn
P Jeffrey
PJ
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D014982:Xenopus laevis
D018690:Excitatory Amino Acid Agonists; C578937:Grm5 protein, rat; D010716:Phosphatidylinositols; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D011493:Protein Kinase C; C010117:3,4-dihydroxyphenylglycol