Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.

Cristina Alcacer (1) , Emanuela Santini (2) , Emmanuel Valjent (1, 3) , Florence Gaven (1, 3) , Jean-Antoine Girault (1) , Denis Hervé (1)

1 Institut du Fer à Moulin
2 CNS - Center for Neural Science [New York]
3 IGF - Institut de Génomique Fonctionnelle

Although l-3,4-dihydroxyphenylalanine (l-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by l-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, l-DOPA activates DA D(1) receptor (D(1)R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D(1)R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα(olf) levels in hemiparkinsonian mice are correlated with LID after chronic l-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα(olf) (Gnal(+/-)). Despite an increase in the lesioned striatum, Gα(olf) levels remained below those of unlesioned wild-type mice. In Gnal(+/-) mice, the lesion-induced l-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal(+/+) and Gnal(+/-) mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα(olf) upregulation is critical for the activation by l-DOPA of D(1)R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of l-DOPA-induced ERK activation in Gnal(+/-) mice supports its causal role in LID development.

Domains: Neurobiology

Cristina Alcacer, Emanuela Santini, Emmanuel Valjent, Florence Gaven, Jean-Antoine Girault, et al.. Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.. Journal of Neuroscience, 2012, 32 (17), pp.5900-10. ⟨10.1523/JNEUROSCI.0837-12.2012⟩. ⟨hal-00693318⟩