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.
journal_name
Exp Neuroljournal_title
Experimental neurologyauthors
Ahmed MR,Bychkov E,Kook S,Zurkovsky L,Dalby KN,Gurevich EVdoi
10.1016/j.expneurol.2015.02.008subject
Has Abstractpub_date
2015-04-01 00:00:00pages
42-54eissn
0014-4886issn
1090-2430pii
S0014-4886(15)00030-8journal_volume
266pub_type
杂志文章abstract::The effect of corporal hypothermia on regional blood flow in peripheral nerve is unknown. We compared blood flow in resting sciatic nerves of anesthetized, normothermic rats with that of rats whose rectal temperatures had been acutely lowered to 28 to 30 degrees C. Peripheral nerve regional blood flow in normothermic ...
journal_title:Experimental neurology
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