J. Neurochem. (2010) 114, 739–749.

Regulator of G protein signaling 9‐2 (RGS9‐2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9‐2 can be found co‐localized with D₂‐class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9‐2 and D₂‐like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9‐2 can specifically co‐localize with D₂‐dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9‐2 for regulating D2R cellular functions: the expression of RGS9‐2 inhibits dopamine‐mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist‐mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9‐2 expression. We utilized mutant constructs of RGS9‐2 to show that the RGS9‐2 DEP (for Disheveled, EGL‐10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9‐2 were necessary for mediating specific inhibition of D2R internalization.