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l ‐DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice
Author(s) -
Santini Emanuela,
Alcacer Cristina,
Cacciatore Silvia,
Heiman Myriam,
Hervé Denis,
Greengard Paul,
Girault JeanAntoine,
Valjent Emmanuel,
Fisone Gilberto
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05831.x
Subject(s) - medium spiny neuron , mapk/erk pathway , striatum , dopamine , microbiology and biotechnology , phosphorylation , chemistry , kinase , dopamine receptor d2 , dopamine receptor , biology , endocrinology , medicine
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.