title: Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats.
abstract: l-DOPA therapy in Parkinson's disease often results in side effects such as l-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to l-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naïve than in chronically l-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to l-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute l-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr(308). Finally, GRK6 reduced accumulation of ΔFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: M Rafiuddin
authors: MR
authors: Ahmed
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Evgeny
authors: E
authors: Bychkov
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Seunghyi
authors: S
authors: Kook
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Lilia
authors: L
authors: Zurkovsky
authors: Division of Medicinal Chemistry, University of Texas at Austin, Austin, TX 78712, USA.
authors: Kevin N
authors: KN
authors: Dalby
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: Eugenia.Gurevich@vanderbilt.edu.
authors: Eugenia V
authors: EV
authors: Gurevich
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000172:deficiency; D015259:Dopamine Agents / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000523:psychology; D054768:G-Protein-Coupled Receptor Kinases / Q000096:biosynthesis*; D007980:Levodopa / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015259:Dopamine Agents; D016760:Proto-Oncogene Proteins c-fos; D007980:Levodopa; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine
keywords: Akt; ERK1/2; GRK6; JNK; Lentivirus; Parkinson's disease; l-DOPA-induced dyskinesia; p38; ΔFosB