RGS9-2 mediates specific inhibition of agonist-induced internalization of D2-dopamine receptors.
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 D(2)-class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D(2)-like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D(2)-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.
Celver
Jeremy
J
Department of Biomedical and Pharmacological Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Sharma
Meenakshi
M
Kovoor
Abraham
A
D000818:Animals; D002460:Cell Line; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D020710:RGS Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014982:Xenopus laevis
D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D020710:RGS Proteins; D017448:Receptors, Dopamine D2; C116925:regulator of g-protein signaling 9; D004298:Dopamine