RT Journal Article
SR Electronic
T1 Coffee, Caffeine, and DARPP-32
JF Science's STKE
JO Sci. STKE
FD American Association for the Advancement of Science
SP tw303
OP tw303
DO 10.1126/stke.2002.146.tw303
VO 2002
IS 146
YR 2002
UL http://stke.sciencemag.org/content/2002/146/tw303.abstract
AB Caffeine is a well-known psychostimulant that increases motor activity by inhibiting the action of the neuromodulator adenosine. By binding to adenosine receptors (A1 and A2A) present in inhibitory neurons in the brain, caffeine prevents activated A2A receptors from initiating a signaling pathway that triggers cAMP production and protein kinase A (PKA) activation. Lindskog et al. report the behavioral effects of caffeine are no longer observed in mice lacking the cytosolic protein DARPP-32. This is because caffeine increases the phosphorylation of DARPP-32 on a specific threonine residue. By blocking the cAMP-PKA pathway, caffeine decreases the action of the protein phosphatase 2A on DARPP-32. Phosphorylated DARPP-32 can then further inhibit PKA activity, amplifying the shutdown of the cAMP-PKA pathway. The effect likely includes a lower level of phosphorylated target proteins of PKA that regulate nerve activity. M. Lindskog, P. Svenningsson, L. Pozzi, Y. Kim, A. A. Fienberg, J. A. Bibb B. B. Fredholm, A. C. Nairn, P. Greengard, G. Fisone, Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature 418, 774-778 (2002). [Online Journal]