title: Regulation of AMPA receptor dephosphorylation by glutamate receptor agonists.
abstract: Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 at Ser(845) enhances AMPA channel activity. This study demonstrates that Ser(845) is rapidly dephosphorylated upon AMPA receptor activation in nucleus accumbens slices. AMPA-induced dephosphorylation at Ser(845) was blocked by CNQX, an AMPA receptor antagonist, by nifedipine, an L-type Ca(2+) channel antagonist, or by cyclosporin A, a calcineurin inhibitor. N-methyl-D-aspartate (NMDA) treatment also decreased phosphorylation of Ser(845), an effect that was blocked by MK-801, an NMDA receptor antagonist, but not by nifedipine. Accumbens neurons are enriched for dopamine- and cyclic AMP (cAMP)-regulated phosphoprotein, Mr 32,000 (DARPP-32), a potent inhibitor of protein phosphatase 1 (PP1) when phosphorylated by PKA (at Thr(34)). We tested the hypothesis that the AMPA/KA or NMDA-stimulated dephosphorylation of DARPP-32 via calcineurin, leading to increased PP1 activity and dephosphorylation of GluR1. AMPA or NMDA treatment decreased phospho-Thr(34)-DARPP-32 levels, effects that were blocked by receptor antagonists, or cyclosporin A. However, dephosphorylation of Ser(845) mediated by AMPA or NMDA receptors was unaffected in DARPP-32/inhibitor-1 knockout mice. These data suggest that AMPA- or NMDA-induced dephosphorylation of GluR1 at Ser(845) occurs by a mechanism that is independent of DARPP-32 and PP1, but involves activation of calcineurin. Thus, Ca(2+)-dependent dephosphorylation of GluR1 may serve as a negative feedback mechanism for the regulation of AMPA receptor activity in neurons.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. gsnyder@intracellulartherapies.com
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.forename: Stacey
authors.initials: S
authors.lastname: Galdi
authors.forename: Allen A
authors.initials: AA
authors.lastname: Fienberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Allen
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
mesh_terms: D000818:Animals; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists* / Q000378:metabolism*
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D018091:Receptors, AMPA