Glutamate counteracts Dopamine/PKA signaling via dephosphorylation of DARPP-32 Ser-97 and alteration of its cytonuclear distribution

Nishi, Akinori, Matamales, Miriam, Musante, Veronica, Valjent, Emmanuel, Kuroiwa, Mahomi, Kitahara, Yosuke, Rebholz, Heike, Greengard, Paul, Girault, Jean-Antoine and Nairn, Angus C. (2017) Glutamate counteracts Dopamine/PKA signaling via dephosphorylation of DARPP-32 Ser-97 and alteration of its cytonuclear distribution. Journal of Biological Chemistry, 292 4: 1462-1476. doi:10.1074/jbc.M116.752402


Author Nishi, Akinori
Matamales, Miriam
Musante, Veronica
Valjent, Emmanuel
Kuroiwa, Mahomi
Kitahara, Yosuke
Rebholz, Heike
Greengard, Paul
Girault, Jean-Antoine
Nairn, Angus C.
Title Glutamate counteracts Dopamine/PKA signaling via dephosphorylation of DARPP-32 Ser-97 and alteration of its cytonuclear distribution
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2017-01-27
Sub-type Article (original research)
DOI 10.1074/jbc.M116.752402
Open Access Status Not yet assessed
Volume 292
Issue 4
Start page 1462
End page 1476
Total pages 15
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2018
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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