Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons

James A. Bibb, Gretchen L. Snyder, Akinori Nishi, Zhen Yan, Laurent Meijer, Allen A. Fienberg, Li-Huei Tsai, Young T. Kwon, Jean-Antoine Girault, Andrew J. Czernik, Richard L. Huganir, Hugh C. Hemmings, Angus C. Nairn and Paul Greengard ()
Additional contact information
James A. Bibb: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Gretchen L. Snyder: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Akinori Nishi: Kurume University School of Medicine
Zhen Yan: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Laurent Meijer: Centre National de la Recherché Scientifique, Station Biologique
Allen A. Fienberg: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Li-Huei Tsai: Harvard Medical School
Young T. Kwon: Harvard Medical School
Jean-Antoine Girault: INSERM U114, Collège de France
Andrew J. Czernik: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Richard L. Huganir: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Hugh C. Hemmings: Weill Medical College of Cornell University
Angus C. Nairn: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Paul Greengard: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University

Nature, 1999, vol. 402, issue 6762, 669-671

Abstract: Abstract The physiological state of the cell is controlled by signal transduction mechanisms which regulate the balance between protein kinase and protein phosphatase activities1. Here we report that a single protein can, depending on which particular amino-acid residue is phosphorylated, function either as a kinase or phosphatase inhibitor. DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34 (refs 2, 3). We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. Decreasing phospho-Thr 75 DARPP-32 in striatal slices, either by a Cdk5-specific inhibitor or by using genetically altered mice, results in increased dopamine-induced phosphorylation of PKA substrates and augmented peak voltage-gated calcium currents. Thus DARPP-32 is a bifunctional signal transduction molecule which, by distinct mechanisms, controls a serine/threonine kinase and a serine/threonine phosphatase.

Date: 1999
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DOI: 10.1038/45251

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