title: GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson's disease via its RGS homology domain.
abstract: 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.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Bychkov
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Lingyong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000209:etiology / Q000378:metabolism*; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D007980:Levodopa / Q000378:metabolism*; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D020710:RGS Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction
chemical_list: D020710:RGS Proteins; D034741:RNA, Small Interfering; D007980:Levodopa; D054770:G-Protein-Coupled Receptor Kinase 3