L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice.
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 D(2) receptor (Drd2-EGFP mice) or the dopamine D(1) 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 D(1) 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.
Santini
Emanuela
E
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Alcacer
Cristina
C
Cacciatore
Silvia
S
Heiman
Myriam
M
Hervé
Denis
D
Greengard
Paul
P
Girault
Jean-Antoine
JA
Valjent
Emmanuel
E
Fisone
Gilberto
G
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D015153:Blotting, Western; D020820:Dyskinesias / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013565:Sympatholytics
D000978:Antiparkinson Agents; D006657:Histones; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases