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J. Biol. Chem., Vol. 278, Issue 2, 1186-1194, January 10, 2003
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From the Spinophilin is a protein phosphatase 1 (PP1)- and
actin-binding protein that modulates excitatory synaptic transmission
and dendritic spine morphology. We report that spinophilin is
phosphorylated in vitro by protein kinase A (PKA).
Phosphorylation of spinophilin was stimulated by treatment of
neostriatal neurons with a dopamine D1 receptor agonist or with
forskolin, consistent with spinophilin being a substrate for PKA in
intact cells. Using tryptic phosphopeptide mapping, site-directed
mutagenesis, and microsequencing analysis, we identified two major
sites of phosphorylation, Ser-94 and Ser-177, that are located within
the actin-binding domain of spinophilin. Phosphorylation of spinophilin
by PKA modulated the association between spinophilin and the actin
cytoskeleton. Following subcellular fractionation, unphosphorylated
spinophilin was enriched in the postsynaptic density, whereas a pool of
phosphorylated spinophilin was found in the cytosol. F-actin
co-sedimentation and overlay analysis revealed that phosphorylation of
spinophilin reduced the stoichiometry of the spinophilin-actin
interaction. In contrast, the ability of spinophilin to bind to PP1
remained unchanged. Taken together, our studies suggest that
phosphorylation of spinophilin by PKA modulates the anchoring of
the spinophilin-PP1 complex within dendritic spines, thereby likely
contributing to the efficacy and plasticity of synaptic transmission.
Phosphorylation of Spinophilin Modulates Its Interaction with
Actin Filaments*
§,,,
**, and
Laboratory of Molecular and Cellular
Neuroscience, The Rockefeller University, New York, New York 10021, the
§ Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, the
¶ Department of Experimental Medicine, Section of Human
Physiology, University of Genova, Genova I-16132, Italy, and the
Department of Psychiatry, School of Medicine, Yale University,
New Haven, Connecticut 06508
*
This work was supported by United States Public Health
Services Grants MH40899 and DA10044 and by Fellowship DRG-1451 of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (to
L. C. H.-W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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