title: Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution.
abstract: The interaction of glutamate and dopamine in the striatum is heavily dependent on signaling pathways that converge on the regulatory protein DARPP-32. The efficacy of dopamine/D1 receptor/PKA signaling is regulated by DARPP-32 phosphorylated at Thr-34 (the PKA site), a process that inhibits protein phosphatase 1 (PP1) and potentiates PKA action. Activation of dopamine/D1 receptor/PKA signaling also leads to dephosphorylation of DARPP-32 at Ser-97 (the CK2 site), leading to localization of phospho-Thr-34 DARPP-32 in the nucleus where it also inhibits PP1. In this study the role of glutamate in the regulation of DARPP-32 phosphorylation at four major sites was further investigated. Experiments using striatal slices revealed that glutamate decreased the phosphorylation states of DARPP-32 at Ser-97 as well as Thr-34, Thr-75, and Ser-130 by activating NMDA or AMPA receptors in both direct and indirect pathway striatal neurons. The effect of glutamate in decreasing Ser-97 phosphorylation was mediated by activation of PP2A. In vitro phosphatase assays indicated that the PP2A/PR72 heterotrimer complex was likely responsible for glutamate/Ca2+-regulated dephosphorylation of DARPP-32 at Ser-97. As a consequence of Ser-97 dephosphorylation, glutamate induced the nuclear localization in cultured striatal neurons of dephospho-Thr-34/dephospho-Ser-97 DARPP-32. It also reduced PKA-dependent DARPP-32 signaling in slices and in vivo Taken together, the results suggest that by inducing dephosphorylation of DARPP-32 at Ser-97 and altering its cytonuclear distribution, glutamate may counteract dopamine/D1 receptor/PKA signaling at multiple cellular levels.
authors.affiliation: From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan, nishia@med.kurume-u.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Institut du Fer à Moulin, INSERM, UPMC UMR-S839, 75005 Paris, France.
authors.forename: Miriam
authors.initials: M
authors.lastname: Matamales
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
authors.forename: Veronica
authors.initials: V
authors.lastname: Musante
authors.affiliation: Institut de Génomique Fonctionnelle, Inserm U1191, UMR 5203 CNRS, Montpellier University, 34094 Montpellier, France, and.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.affiliation: From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Mahomi
authors.initials: M
authors.lastname: Kuroiwa
authors.affiliation: From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kitahara
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065.
authors.forename: Heike
authors.initials: H
authors.lastname: Rebholz
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Institut du Fer à Moulin, INSERM, UPMC UMR-S839, 75005 Paris, France.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D017447:Receptors, Dopamine D1; D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2; D004298:Dopamine
keywords: CK2; DARPP-32; dopamine; glutamate; nuclear translocation; protein kinase A (PKA); protein phosphatase 2 (PP2A); protein phosphorylation; striatum