L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


In the dopamine-depleted striatum, extracellular signal-regulated kinase (ERK) signaling is implicated in the development of l-DOPA-induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l-DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D2 receptor (Drd2-EGFP mice) or the dopamine D1 receptor (Drd1a-EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6-hydroxydopamine-lesioned Drd2-EGFP mice, l-DOPA increased the phosphorylation of ERK, mitogen- and stress-activated kinase 1 and histone H3, selectively in EGFP-negative MSNs. Conversely, a complete co-localization between EGFP and these phosphoproteins was observed in Drd1a-EGFP mice. The effect of l-DOPA was prevented by blockade of dopamine D1 receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l-DOPA. Our results demonstrate that in the dopamine-depleted striatum, l-DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK-dependent changes in striatal plasticity leading to dyskinesia.


  • Emanuela Santini
  • Cristina Alcacer
  • Silvia Cacciatore
  • Myriam Heiman
  • Denis Hervé
  • Paul Greengard
  • Jean-Antoine Girault
  • Emmanuel Valjent
  • Gilberto Fisone
Externa organisationer
  • Karolinska Institute
  • Rockefeller University
  • Pierre and Marie Curie University


Sidor (från-till)621-633
Antal sidor13
TidskriftJournal of Neurochemistry
Utgåva nummer3
StatusPublished - 2009 feb
Peer review utfördJa
Externt publiceradJa