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: Emanuela Santini, Michael Feyder, Giuseppe Gangarossa, Helen S Bateup, Paul Greengard, Gilberto Fisone
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 33 Pg. 27806-12 (Aug 10 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22753408 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiparkinson Agents
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Multiprotein Complexes
• Nerve Tissue Proteins
• Ppp1r1b protein, mouse
• Proteins
• Levodopa
• Cyclic AMP
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• Dopamine

Topics

• Animals
• Antiparkinson Agents (pharmacology)
• Cyclic AMP (genetics, metabolism)
• Dopamine (genetics, metabolism)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (genetics, metabolism)
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Humans
• Levodopa (pharmacology)
• MAP Kinase Signaling System
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Transgenic
• Multiprotein Complexes
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (metabolism)
• Parkinsonian Disorders (drug therapy, genetics, metabolism)
• Proteins (genetics, metabolism)
• TOR Serine-Threonine Kinases