title: Gα(olf) mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in L-3,4-dihydroxyphenylalanine-induced dyskinesia.
abstract: 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 D₁ receptor(D₁R) 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, D₁R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and inpatients. 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 D₁R-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.
authors.affiliation: Inserm UMR-S 839, F-75005 Paris, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alcacer
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.forename: Florence
authors.initials: F
authors.lastname: Gaven
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001545:Benserazide / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007839:Functional Laterality / Q000187:drug effects; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009068:Movement / Q000187:drug effects; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D001545:Benserazide; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D044385:GTP-Binding Protein alpha Subunits; D006657:Histones; D007980:Levodopa; D016627:Oxidopamine; D018091:Receptors, AMPA; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase; C084618:olfactory G protein subunit alpha olf