title: Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism.
abstract: Dyskinesia, a motor complication caused by prolonged administration of the antiparkinsonian drug l-3,4-dihydroxyphenylalanine (l-DOPA), is accompanied by activation of cAMP signaling and hyperphosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Here, we show that the abnormal phosphorylation of DARPP-32 occurs specifically in medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1R). Using mice in which DARPP-32 is selectively deleted in D1R-expressing MSNs, we demonstrate that this protein is required for l-DOPA-induced activation of the extracellular signal-regulated protein kinases 1 and 2 and the mammalian target of rapamycin complex 1 (mTORC1) pathways, which are implicated in dyskinesia. We also show that mutation of the phosphorylation site for cAMP-dependent protein kinase on DARPP-32 attenuates l-DOPA-induced dyskinesia and reduces the concomitant activations of ERK and mTORC1 signaling. These studies demonstrate that, in D1R-expressing MSNs, l-DOPA-induced activation of ERK and mTORC1 requires DARPP-32 and indicates the importance of the cAMP/DARPP-32 signaling cascade in dyskinesia.
authors: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors: Emanuela
authors: E
authors: Santini
authors: Michael
authors: M
authors: Feyder
authors: Giuseppe
authors: G
authors: Gangarossa
authors: Helen S
authors: HS
authors: Bateup
authors: Paul
authors: P
authors: Greengard
authors: Gilberto
authors: G
authors: Fisone
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000978:Antiparkinson Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C497929:Ppp1r1b protein, mouse; D011506:Proteins; D007980:Levodopa; D000242:Cyclic AMP; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine