DARPP-32 and modulation of cAMP signaling: involvement in motor control and levodopa-induced dyskinesia.
The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is abundantly expressed in the medium spiny neurons of the striatum. Phosphorylation catalysed by cAMP-dependent protein kinase (PKA) converts DARPP-32 into an inhibitor of protein phosphatase-1. In contrast, phosphorylation catalysed by cyclin dependent kinase-5 on Thr75 converts DARPP-32 into an inhibitor of PKA. Changes in the state of phosphorylation of DARPP-32 reinforce the behavioral effects produced by stimulation or inhibition of the cAMP pathway. Dopamine, via D(1) receptors, and adenosine, via A(2A) receptors, affect motor behavior by acting on medium spiny neurons, via G(olf) mediated stimulation of the cAMP signaling cascade. The involvement of DARPP-32 in dopamine and adenosine transmission and the possible role played by abnormal regulation of DARPP-32 phosphorylation in levodopa-induced dyskinesia are discussed.
Håkansson
Kerstin
K
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, S-17177 Stockholm, Sweden.
Lindskog
Maria
M
Pozzi
Laura
L
Usiello
Alessandro
A
Fisone
Gilberto
G
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000633:toxicity; D009043:Motor Activity / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D007980:Levodopa; D000242:Cyclic AMP