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

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 GRK(3) in the striatum, whereas knockdown of GRK(3) by microRNA exacerbated it. Kinase-dead GRK(3) and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK(3) with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK(3), kinase-dead GRK(3), and RH inhibited accumulation of Delta FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK(3) knockdown exacerbated Delta FosB accumulation. Our findings reveal a novel mechanism of GRK(3) control of the dopamine receptor signaling and the role of Gq in LID.