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The role of kinase and RGS activity of GRKs in regulating the dopaminergic signaling in hemiparkinsonian rats
Author(s) -
Ahmed Mohamed Rafiuddin,
Gurevich Vsevolod V,
Gurevich Eugenia V
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1172.11
Subject(s) - g protein coupled receptor kinase , beta adrenergic receptor kinase , dopaminergic , dopamine receptor , microbiology and biotechnology , signal transduction , neuroscience , g protein coupled receptor , chemistry , dopamine , pharmacology , biology
L‐DOPA is the treatment of choice for Parkinson's disease (PD) but prolonged exposure to the drug often leads to exaggerated signaling via dopamine (DA) receptors and motor complications such as L‐DOPA‐induced dyskinesia (LID). DA receptors are desensitized via activation‐dependent receptor phosphorylation by GRKs followed by the binding of arrestins, which stops further signal transduction. We previously reported that elevated expression of GRK6 in the striatum (Ahmed et al, 2010, Sci Trans Med, 2(28), 28ra28) ameliorated LID by promoting desensitization of DA receptors. Now we confirm that GRK6 acts via phosphorylation, since kinase‐dead protein mutant was without effect. Another GRK isoform, GRK3, potently inhibited L‐DOPA‐induced contralateral rotations in hemiparkinsonian rats. In contrast to GRK6, kinase‐dead GRK3 mutant suppressed rotations as effectively as wild type GRK3. This had prompted us to test the hypothesis that the GRK3 act via its RGS domain known to down regulate the signaling by sequestering Gaq/11. To address this question we used separate GRK3 RGS domain and RGS dead GRK3 constructs in the unilateral 6‐OHDA lesioned rat model. GRK3 RGS countered the rotational behavior, whereas the RGS‐dead GRK3 was ineffective. The data demonstrate that GRK3 regulates dopaminergic signaling and behavioral sensitization to L‐DOPA via its RGS domain. Grant Support: NS45117 and NS065868 to EVG