Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9 -2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9 -2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9 -2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9 -2 overexpression -achieved by viral vector injection into the striatum -diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9 -2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9 -2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9 Ϫ/Ϫ mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9 ϩ/ϩ mice, albeit the rotational behavior -taken as an index of the anti-parkinsonian response -is similar between the two groups of mice. Together, these findings suggest that RGS9 -2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9 -2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.

RGS9-2 is a striatum-enriched protein that negatively modulates dopamine and opioid receptor signaling. We examined the role of RGS9-2 in modulating complex behavior. Genetic deletion of RGS9-2 does not lead to global impairments, but results in selective abnormalities in certain behavioral domains. RGS9 knockout (KO) mice have decreased motor coordination on the accelerating rotarod and deficits in working memory as measured in the delayed-match to place version of the water maze. In contrast, RGS9 KO mice exhibit normal locomotor activity, anxietylike behavior, cue and contextual fear conditioning, startle threshold, and pre-pulse inhibition. These studies are the first to describe a role for RGS9-2 in motor coordination and working memory and implicate RGS9-2 as a potential therapeutic target for motor and cognitive dysfunction. KeywordsRGS9; motor coordination; working memory; delayed-match to place water maze; dopamine; striatum IntroductionThe regulators of G protein signaling (RGS) family of proteins negatively modulate heterotrimeric G protein signaling by stimulating the GTPase activity of G protein α subunits (Berman and Gilman, 1998) and can function as effector molecules in certain signaling networks (De Vries et al., 2000). RGS proteins also regulate cellular excitability via their indirect modulation of G-protein-coupled inwardly rectifying K+ channels (GIRK) and voltage-dependent calcium channels (Berman et al., 1996;Chuang et al., 1998;Doupnik et al., 1997;Hollinger and Hepler, 2002;Sondek and Siderovski, 2001;Zhou et al., 2000).The greater than 25 mammalian RGS proteins identified to date are defined by their 120 amino acid RGS domain and can be organized into subfamilies based on structural features and relative specificity for different G-protein subunits (Traynor and Neubig, 2005). Numerous RGS genes are expressed in brain with highly region-specific expression patterns (Dohlman and Thorner, 1997). The biological role of specific RGS proteins is currently an area of active research.

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