Association of Protein Phosphatase 1gamma1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model Export

@article{citeulike:3214196, abstract = {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{alpha} (CaMKII{alpha}). 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{alpha}. 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 PP1{gamma}1 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. PP1{gamma}1). However, total striatal levels of PP1{gamma}1 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 PP1{gamma}1 with spinophilin in striatal extracts. In combination, these data demonstrate that striatal dopamine depletion inhibits a specific synaptic phosphatase by increasing PP1{gamma}1 interaction with spinophilin, perhaps contributing to hyperphosphorylation of synaptic proteins and disruptions of synaptic plasticity and/or dendritic morphology. 10.1074/jbc.M801377200}, author = {Brown, Abigail M. and Baucum, Anthony J. and Bass, Martha A. and Colbran, Roger J.}, citeulike-article-id = {3214196}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M801377200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/283/21/14286}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18372251}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18372251}, day = {23}, doi = {10.1074/jbc.M801377200}, journal = {J. Biol. Chem.}, keywords = {neurology, parkinsons, phosphatase-1}, month = {May}, number = {21}, pages = {14286--14294}, posted-at = {2008-09-10 23:51:29}, priority = {2}, title = {Association of Protein Phosphatase 1{gamma}1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model}, url = {http://dx.doi.org/10.1074/jbc.M801377200}, volume = {283}, year = {2008} }

TY - JOUR ID - citeulike:3214196 L3 - citeulike-article-id:3214196 N2 - 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{alpha} (CaMKII{alpha}). 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{alpha}. 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 PP1{gamma}1 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. PP1{gamma}1). However, total striatal levels of PP1{gamma}1 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 PP1{gamma}1 with spinophilin in striatal extracts. In combination, these data demonstrate that striatal dopamine depletion inhibits a specific synaptic phosphatase by increasing PP1{gamma}1 interaction with spinophilin, perhaps contributing to hyperphosphorylation of synaptic proteins and disruptions of synaptic plasticity and/or dendritic morphology. 10.1074/jbc.M801377200 IS - 21 JF - J. Biol. Chem. EP - 14294 TI - Association of Protein Phosphatase 1{gamma}1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model VL - 283 SP - 14286 KW - neurology KW - parkinsons KW - phosphatase-1 AU - Brown, Abigail AU - Baucum, Anthony AU - Bass, Martha AU - Colbran, Roger PY - 2008/05/23/ UR - http://dx.doi.org/10.1074/jbc.M801377200 ER -