Dopamine-induced arrestin recruitment and desensitization of the dopamine D4 receptor is regulated by G protein-coupled receptor kinase-2.

The dopamine D₄ receptor (D₄R) is expressed in the retina, prefrontal cortex, and autonomic nervous system and has been implicated in attention deficit hyperactivity disorder (ADHD), substance use disorders, and erectile dysfunction. D₄R has also been investigated as a target for antipsychotics due to its high affinity for clozapine. As opposed to the closely related dopamine D₂ receptor (D2R), dopamine-induced arrestin recruitment and desensitization at the D₄R have not been studied in detail. Indeed, some earlier investigations could not detect arrestin recruitment and desensitization of this receptor upon its activation by agonist. Here, we used a novel nanoluciferase complementation assay to study dopamine-induced recruitment of β-arrestin2 (βarr2; also known as arrestin3) and G protein-coupled receptor kinase-2 (GRK2) to the D₄R in HEK293T cells. We also studied desensitization of D₄R-evoked G protein-coupled inward rectifier potassium (GIRK; also known as Kir3) current responses in Xenopus oocytes. Furthermore, the effect of c-oexpression of GRK2 on βarr2 recruitment and GIRK response desensitization was examined. The results suggest that co-expression of GRK2 enhanced the potency of dopamine to induce βarr2 recruitment to the D₄R and accelerated the rate of desensitization of D₄R-evoked GIRK responses. The present study reveals new details about the regulation of arrestin recruitment to the D₄R and thus increases our understanding of the signaling and desensitization of this receptor. [ABSTRACT FROM AUTHOR]