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J. Biol. Chem., Vol. 283, Issue 21, 14286-14294, May 23, 2008

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Association of Protein Phosphatase 1₁ with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model^*

Abigail M. Brown, Anthony J. Baucum¹, Martha A. Bass, and Roger J. Colbran^¶2

From the Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, ^¶Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232

Sustained nigrostriatal dopamine depletion increases the serine/threonine phosphorylation of multiple striatal proteins that play a role in corticostriatal synaptic plasticity, including Thr²⁸⁶ phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). Mechanisms underlying these changes are unclear, but protein phosphatases play a critical role in the acute modulation of striatal protein phosphorylation. Here we show that dopamine depletion for periods ranging from 3 weeks to 10 months significantly reduces the total activity of protein phosphatase (PP) 1, but not of PP2A, in whole lysates of rat striatum, as measured using multiple substrates, including Thr²⁸⁶-autophosphorylated CaMKII. Striatal PP1 activity is partially inhibited by a fragment of the PP1-binding protein neurabin-I, Nb-(146–493), because of the selective inhibition of the PP1₁ isoform. The fraction of PP1 activity that is insensitive to Nb-(146–493) was unaffected by dopamine depletion, demonstrating that dopamine depletion specifically reduces the activity of PP1 isoforms that are sensitive to Nb-(146–493) (i.e. PP1₁). However, total striatal levels of PP1₁ or any other PP1 isoform were unaffected by dopamine depletion, and our previous studies showed that total levels of the PP1 regulatory/targeting proteins DARPP-32, spinophilin, and neurabin were also unchanged. Rather, co-immunoprecipitation experiments demonstrated that dopamine depletion increases the association of PP1₁ with spinophilin in striatal extracts. In combination, these data demonstrate that striatal dopamine depletion inhibits a specific synaptic phosphatase by increasing PP1₁ interaction with spinophilin, perhaps contributing to hyperphosphorylation of synaptic proteins and disruptions of synaptic plasticity and/or dendritic morphology.

Received for publication, February 20, 2008 , and in revised form, March 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants PO1-NS044282 and RO1-MH63232. This work was also supported by the Parkinson Foundation Center of Excellence at Vanderbilt University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Neurogenomics Training Program funded by the National Institutes of Health Grant T32-MH65215.

² To whom correspondence should be addressed: Rm. 702 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Tel.: 615-936-1630; Fax: 615-322-7236; E-mail: roger.colbran{at}vanderbilt.edu.

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