Striatal spinophilin enhances dopamine D2 receptor (D2R) interaction with cytosolic proteins to mediate persistent D2R agonist-induced locomotor suppression.

Loss of dopamine neurons in Parkinson disease (PD) leads to motor deficits. Dopamine D2 receptor (D2R) agonists treat PD-associated motor deficits by acting on postsynaptic receptors located within the striatum that have been upregulated due dopamine loss. However, mechanisms that contribute to increased D2R activity in PD to enhance D2R function are poorly described. Spinophilin is a protein phosphatase 1 targeting protein that is expressed in postsynaptic dendritic spines and interacts with postsynaptic D2Rs. However, how spinophilin regulates D2R function is unknown. In the current study, we found that loss of spinophilin, specifically in indirect pathway medium spiny neurons and cholinergic interneurons limited the suppression of locomotion caused by the D2R agonist, quinpirole. Mechanistically, using proximity labeling in neuro2A cells and coimmunoprecipitaitons in striatal lysates from wildtype and spinophilin knockout mice, we found that spinophilin promotes the interaction of the D2R with intracellular proteins, suggesting spinophilin mediates agonist-induced D2R internalization. Therefore, our data support future studies targeting the spinophilin/D2R interaction to enhance D2R agonist activity, which may promote the efficacy of current PD therapeutics. SIGNIFICANCE STATEMENT: This manuscript demonstrates that spinophilin mediates agonist-induced D2R protein interactions with intracellular proteins and locomotor suppression. The study delineates spinophilin as a potential target to enhance the efficacy of D2R agonists, a mainstay treatment for Parkinson disease.