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Letters to Nature

Nature 418, 774-778 (15 August 2002) | doi:10.1038/nature00817; Received 21 February 2002; Accepted 3 April 2002

Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine

Maria Lindskog1, Per Svenningsson2, Laura Pozzi1,3, Yong Kim2, Allen A. Fienberg2, James A. Bibb2,3, Bertil B. Fredholm4, Angus C. Nairn2, Paul Greengard2 & Gilberto Fisone1

  1. Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
  2. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA
  3. Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
  4. Present addresses: Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, Milan, Italy (L.P.); Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA (J.A.B)

Correspondence to: Gilberto Fisone1 Correspondence and requests for materials should be addressed to G.F. (e-mail: Email: gilberto.fisone@neuro.ki.se).

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Caffeine has been imbibed since ancient times in tea and coffee, and more recently in colas. Caffeine owes its psychostimulant action to a blockade of adenosine A2A receptors1, but little is known about its intracellular mechanism of action. Here we show that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000)2. Results virtually identical to those seen with caffeine were obtained with the selective A2A antagonist SCH 58261. The depressant effect of the A2A receptor agonist, CGS 21680, on motor activity was also greatly attenuated in DARPP-32 knockout mice. In support of a role for DARPP-32 in the action of caffeine, we found that, in striata of intact mice, caffeine increased the state of phosphorylation of DARPP-32 at Thr 75. Caffeine increased Thr 75 phosphorylation through inhibition of PP-2A-catalysed dephosphorylation, rather than through stimulation of cyclin-dependent kinase 5 (Cdk5)-catalysed phosphorylation, of this residue. Together, these studies demonstrate the involvement of DARPP-32 and its phosphorylation/dephosphorylation in the stimulant action of caffeine.