GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson's disease via its RGS homology domain.

Ahmed MR, Bychkov E, Li L, Gurevich VV, Gurevich EV
Sci Rep. 2015 5: 10920

PMID: 26043205 · PMCID: PMC4455246 · DOI:10.1038/srep10920

Degeneration of dopaminergic neurons causes Parkinson's disease. Dopamine replacement therapy with L-DOPA is the best available treatment. However, patients develop L-DOPA-induced dyskinesia (LID). In the hemiparkinsonian rat, chronic L-DOPA increases rotations and abnormal involuntary movements modeling LID, via supersensitive dopamine receptors. Dopamine receptors are controlled by G protein-coupled receptor kinases (GRKs). Here we demonstrate that LID is attenuated by overexpression of GRK3 in the striatum, whereas knockdown of GRK3 by microRNA exacerbated it. Kinase-dead GRK3 and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK3 with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK3, kinase-dead GRK3, and RH inhibited accumulation of ∆FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK3 knockdown exacerbated ∆FosB accumulation. Our findings reveal a novel mechanism of GRK3 control of the dopamine receptor signaling and the role of Gq in LID.

MeSH Terms (16)

Animals Behavior, Animal Corpus Striatum Disease Models, Animal Dyskinesias G-Protein-Coupled Receptor Kinase 3 Gene Expression Gene Knockdown Techniques Levodopa Parkinson Disease Protein Interaction Domains and Motifs Rats RGS Proteins RNA, Small Interfering RNA Interference Signal Transduction

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