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

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          Abstract

          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 STEP 61, a membrane-associated protein, and STEP 46, a cytosolic protein. The C terminals of these two isoforms are identical, whereas the N-terminal domain of STEP 61 contains a novel 172 amino acid sequence that includes several structural motifs not present in STEP 46. 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 STEP 61 and STEP 46 are phosphorylated on seryl residues by a cAMP-dependent protein kinase (PKA)-mediated pathway in striatal homogenates. The specific residues phosphorylated in STEP 61 were identified by site-directed mutagenesis and tryptic phosphopeptide mapping as Ser160 and Ser221, whereas the major site of phosphorylation in STEP 46 was shown to be Ser49. Ser160 is located within the unique N terminal of STEP 61. Ser221 and Ser49 are equivalent residues present in STEP 61 and STEP 46, 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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          1 August 2000
          : 20
          : 15
          : 5630-5638
          Affiliations
          [ 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
          Article
          PMC6772528 PMC6772528 6772528 4370
          10.1523/JNEUROSCI.20-15-05630.2000
          6772528
          10908600
          8dc7bdab-f887-41dc-938c-b88bbca5dbc3
          Copyright © 2000 Society for Neuroscience
          History
          : 10 January 2000
          : 3 May 2000
          : 11 May 2000
          Categories
          ARTICLE
          Cellular/Molecular
          Custom metadata
          5.00

          dopamine D1 receptor,KIM domain,striatum,dopamine,cAMP-dependent PKA,STEP,signal transduction,protein tyrosine phosphatase,protein tyrosine kinase,basal ganglia

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