age-dependent targeting of protein phosphatase 1 to ca2+calmodulin-dependent protein kinase ii by spinophilin in mouse striatum年龄相关性目标蛋白质磷酸酶1 ca2 + calmodulin-dependent spinophilin蛋白激酶二世的鼠纹状体.pdfVIP

Age-Dependent Targeting of Protein Phosphatase 1 to Ca2+/Calmodulin-Dependent Protein Kinase II by Spinophilin in Mouse Striatum ¤ Anthony J. Baucum II*, Stefan Strack , Roger J. Colbran Department of Molecular Physiology and Biophysics, Vanderbilt-Kennedy Center, Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America Abstract Mechanisms underlying age-dependent changes of dendritic spines on striatal medium spiny neurons are poorly understood. Spinophilin is an F-actin- and protein phosphatase 1 (PP1)-binding protein that targets PP1 to multiple downstream effectors to modulate dendritic spine morphology and function. We found that calcium/calmodulin- dependent protein kinase II (CaMKII) directly and indirectly associates with N- and C-terminal domains of spinophilin, but F- actin can displace CaMKII from the N-terminal domain. Spinophilin co-localizes PP1 with CaMKII on the F-actin cytoskeleton in heterologous cells, and spinophilin co-localizes with synaptic CaMKII in neuronal cultures. Thr286 autophosphorylation enhances the binding of CaMKII to spinophilin in vitro and in vivo. Although there is no change in total levels of Thr286 autophosphorylation, maturation from postnatal day 21 into adulthood robustly enhances the levels of CaMKII that co- immunoprecipitate with spinophilin from mouse striatal extracts. Moreover, N- and C-terminal domain fragments of spinophilin bind more CaMKII from adult vs. postnatal day 21 striatal lysates. Total levels of other proteins that interact with C-terminal domains of spinophilin decrease during maturation, perhaps reducing competition for CaMKII binding