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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antiparkinson Agents / pharmacology
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Cyclic AMP / genetics
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Cyclic AMP / metabolism*
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Dopamine / genetics
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Dopamine / metabolism*
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Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
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Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism*
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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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Levodopa / pharmacology
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MAP Kinase Signaling System*
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Transgenic
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Multiprotein Complexes
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / metabolism*
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Parkinsonian Disorders / drug therapy
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Parkinsonian Disorders / genetics
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Parkinsonian Disorders / metabolism
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Proteins / genetics
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Proteins / metabolism*
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TOR Serine-Threonine Kinases
Substances
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Antiparkinson Agents
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Multiprotein Complexes
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Nerve Tissue Proteins
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Ppp1r1b protein, mouse
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Proteins
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Levodopa
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Cyclic AMP
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Dopamine