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

• Published in: Nature (London) 2002-08, Vol.418 (6899), p.774-778
• Main Authors: Fisone, Gilberto, Lindskog, Maria, Svenningsson, Per, Pozzi, Laura, Kim, Yong, Fienberg, Allen A, Bibb, James A, Fredholm, Bertil B, Nairn, Angus C, Greengard, Paul
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Animals; Biological and medical sciences; Caffeine; Caffeine - administration & dosage; Caffeine - pharmacology; Cellular biology; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - metabolism; Dopamine and cAMP-Regulated Phosphoprotein 32; Genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - drug effects; Neostriatum - cytology; Neostriatum - drug effects; Neostriatum - metabolism; Nerve Tissue Proteins; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Phenethylamines - pharmacology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation - drug effects; Phosphothreonine - metabolism; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Purinergic P1 Receptor Antagonists; Pyrimidines - pharmacology; Receptors, Purinergic P1 - metabolism; Rodents; Stimulants; Triazoles - pharmacology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature00817

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 receptors, 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). 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.