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The Journal of Neuroscience, August 1, 2000, 20(15):5630-5638

The Dopamine/D1 Receptor Mediates the Phosphorylation and Inactivation of the Protein Tyrosine Phosphatase STEP via a PKA-Dependent Pathway

Surojit Paul¹, Gretchen L. Snyder³, Hisayuki Yokakura¹, Marina R. Picciotto², Angus C. Nairn³, and Paul J. Lombroso¹

¹ The Child Study Center and the ² Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, and ³ Rockefeller University, New York, New York 10021

The striatal-enriched protein tyrosine phosphatase (STEP) family is expressed within dopaminoceptive neurons of the CNS and is particularly enriched within the basal ganglia and related structures. Alternative splicing produces several isoforms that are found in a number of subcellular compartments, including postsynaptic densities of medium spiny neurons. The variants include STEP₆₁, a membrane-associated protein, and STEP₄₆, a cytosolic protein. The C terminals of these two isoforms are identical, whereas the N-terminal domain of STEP₆₁ contains a novel 172 amino acid sequence that includes several structural motifs not present in STEP₄₆. Amino acid sequencing revealed a number of potential phosphorylation sites in both STEP isoforms. Therefore, we investigated the role of phosphorylation in regulating STEP activity. Both STEP₆₁ and STEP₄₆ are phosphorylated on seryl residues by a cAMP-dependent protein kinase (PKA)-mediated pathway in striatal homogenates. The specific residues phosphorylated in STEP₆₁ were identified by site-directed mutagenesis and tryptic phosphopeptide mapping as Ser160 and Ser221, whereas the major site of phosphorylation in STEP₄₆ was shown to be Ser49. Ser160 is located within the unique N terminal of STEP₆₁. Ser221 and Ser49 are equivalent residues present in STEP₆₁ and STEP₄₆, respectively, and are located at the center of the kinase-interacting motif that has been implicated in protein-protein interactions. Phosphorylation at this site decreases the activity of STEP in vitro by reducing its affinity for its substrate. In vivo studies using striatal slices demonstrated that the neurotransmitter dopamine leads to the phosphorylation of STEP via activation of D1 receptors and PKA.

Key words: protein tyrosine phosphatase; KIM domain; dopamine; dopamine D1 receptor; cAMP-dependent PKA; STEP; striatum; basal ganglia; protein tyrosine kinase; signal transduction

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155630-09$05.00/0

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