NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin.

Alagarsamy S, Saugstad J, Warren L, Mansuy IM, Gereau RW, Conn PJ
Neuropharmacology. 2005 49 Suppl 1: 135-45

PMID: 16005030 · PMCID: PMC3799794 · DOI:10.1016/j.neuropharm.2005.05.005

Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

MeSH Terms (32)

Animals Autoradiography Brain Calcineurin CHO Cells Cricetinae Cricetulus Dose-Response Relationship, Drug Drug Synergism Electric Stimulation Enzyme Activation Enzyme Inhibitors Excitatory Amino Acid Agonists Glutamic Acid Glutathione Transferase Hydroxylation Immunoblotting Immunoprecipitation Membrane Potentials Methoxyhydroxyphenylglycol Mutagenesis N-Methylaspartate Okadaic Acid Oocytes Patch-Clamp Techniques Phosphatidylinositols Protein Kinase C Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Transfection Xenopus

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