Heteromerization between α_2A adrenoceptors and different polymorphic variants of the dopamine D₄ receptor determines...

Polymorphic alleles of the human dopamine D₄ receptor gene (DRD4) have been consistently associated with individual differences in personality traits and neuropsychiatric disorders, particularly between the gene encoding dopamine D_4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α_2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α_2A adrenoceptor (α_2AR), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D₄ receptor (D₄R) and α_2AR in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D₄R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α_2AR forms functional heteromers with D₄R and weather these heteromers show different properties depending on the D₄R variant involved. Using cortical brain slices from hD_4.7R knock-in and wild-type mice, here, we demonstrate that α_2AR and D₄R heteromerize and constitute a significant functional population of cortical α_2AR and D₄R. Moreover, in cortical slices from wild-type mice and in cells transfected with α_2AR and D_4.4R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD_4.7R knock-in mice and in cells expressing the D_4.7R polymorphic variant. We also show a lack of efficacy of D₄R ligands to promote G protein activation and signaling only within the α_2AR-D_4.7R heteromer. Taken together, our results suggest that α_2AR-D₄R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy.