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The Journal of biological chemistry v.292 no.4, 2017년, pp.1462 - 1476   SCI SCIE
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Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution

Nishi, Akinori (From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan, ); Matamales, Miriam (Institut du Fer à ); Musante, Veronica (Moulin, INSERM, UPMC UMR-S839, 75005 Paris, France, ); Valjent, Emmanuel (Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, ); Kuroiwa, Mahomi (Institut de Gàénomique Fonctionnelle, Inserm U1191, UMR 5203 CNRS, Montpellier University, 34094 Montpellier, France, and ); Kitahara, Yosuke (From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan, ); Rebholz, Heike (From the Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan, ); Greengard, Paul (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065 ); Girault, Jean-Antoine (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065 ); Nairn, Angus C. (Institut du Fer à );
  • 초록  

    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/Ca 2+ -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.


  • 주제어

    dopamine .   glutamate .   nuclear translocation .   protein kinase A (PKA) .   protein phosphatase 2 (PP2A) .   protein phosphorylation .   CK2 .   DARPP-32 .   striatum.  

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