Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution.

The interaction of glutamate and dopamine in the striatum is heavily dependent on signaling pathways that converge on the regulatory protein The efficacy of dopamine/D1 signaling is regulated by phosphorylated at Thr-34 (the site), a process that inhibits protein phosphatase 1 (PP1) and potentiates duanyu1529 action. Activation of dopamine/D1 receptor/duanyu1529 signaling also leads to dephosphorylation of Dduanyu37P-32 at Ser-97 (the CK2 site), leading to localization of phospho-Thr-34 Dduanyu37P-32 in the nucleus where it also inhibits PP1. In this study the role of glutamate in the regulation of Dduanyu37P-32 phosphorylation at four major sites was further investigated. Experiments using striatal slices revealed that glutamate decreased the phosphorylation states of Dduanyu37P-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 Dduanyu37P-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 Dduanyu37P-32. It also reduced Dduanyu37P-32 signaling in slices and in vivo Taken together, the results suggest that by inducing dephosphorylation of Dduanyu37P-32 at Ser-97 and altering its cytonuclear distribution, glutamate may counteract dopamine/D1 receptor/duanyu1529 signaling at multiple cellular levels.

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