Mitogen- and stress-activated protein kinase 1 is required for specific signaling responses in dopamine-denervated mouse striatum, but is not necessary for L-DOPA-induced dyskinesia

In advanced Parkinson's disease, L-DOPA treatment causes the appearance of abnormal involuntary movements or L-DOPA-induced dyskinesia (LID). LID results in part from L-DOPA-induced activation of extracellular signal-regulated kinase (ERK) in the dopamine-denervated striatum. Activated ERK triggers nuclear responses, including phosphorylation of mitogen- and stress-activated protein kinase 1 (MSK1) and histone H3, and transcription of genes such as FosB. To determine the role of MSK1, wild type and MSK1 knockout mice with unilateral 6-hydroxydopamine lesion in the dorsolateral striatum were chronically treated with L-DOPA. The absence of MSK1 had no effect on the lesion or L-DOPA-induced ERK activation, but reduced L-DOPA-induced phospholylation of histone H3 and FosB accumulation in the dopamine-denervated striatum. MSK1 deficiency also prevented the increase in G alpha olf, the stimulatory a subunit of G protein coupling striatal dopamine D1 receptor to adenylyl cyclase. However, the intensity of LID was similar in MSK1-deficient and wild type mice. In conclusion, L-DOPA-induced activation of MSKI contributes to histone H3 phosphorylation, induction of FosB, and Gaolf up-regulation but appears not to be necessary for the development of LID. (C) 2014 Elsevier Ireland Ltd. All rights reserved.