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Gαolf mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in l-3,4-dihydroxyphenylalanine-induced dyskinesia

Alcacer, Cristina LU ; Santini, Emanuela; Valjent, Emmanuel; Gaven, Florence; Girault, Jean-Antoine and Hervé, Denis (2012) In Journal of Neuroscience 32(17). p.5900-5910
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 Gαolf, a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased... (More)

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 Gαolf, a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gαolf 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 Gαolf (Gnal+/-). Despite an increase in the lesioned striatum, Gαolf 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, Gαolf 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.

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published
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Journal of Neuroscience
volume
32
issue
17
pages
11 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:84860158569
ISSN
0270-6474
DOI
10.1523/jneurosci.0837-12.2012
language
English
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no
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d954a4ce-743c-4328-bf4d-6af034c41005
date added to LUP
2017-02-14 16:22:36
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2017-08-10 15:19:55
@article{d954a4ce-743c-4328-bf4d-6af034c41005,
  abstract     = {<p>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<sub>1</sub> receptor (D<sub>1</sub>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<sub>1</sub>R activates adenylyl-cyclase through Gα<sub>olf</sub>, a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα<sub>olf</sub> 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<sub>olf</sub> (Gnal<sup>+/-</sup>). Despite an increase in the lesioned striatum, Gα<sub>olf</sub> levels remained below those of unlesioned wild-type mice. In Gnal<sup>+/-</sup> 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<sup>+/+</sup> and Gnal<sup>+/-</sup> mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα<sub>olf</sub> upregulation is critical for the activation by l-DOPA of D<sub>1</sub>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<sup>+/-</sup> mice supports its causal role in LID development.</p>},
  author       = {Alcacer, Cristina and Santini, Emanuela and Valjent, Emmanuel and Gaven, Florence and Girault, Jean-Antoine and Hervé, Denis},
  issn         = {0270-6474},
  language     = {eng},
  month        = {04},
  number       = {17},
  pages        = {5900--5910},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Gαolf mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in l-3,4-dihydroxyphenylalanine-induced dyskinesia},
  url          = {http://dx.doi.org/10.1523/jneurosci.0837-12.2012},
  volume       = {32},
  year         = {2012},
}