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Heteromerization between α_2A adrenoceptors and different polymorphic variants of the dopamine D₄ receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

ABSTRACT: 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.

SUBMITTER: Casado-Anguera V

PROVIDER: S-EPMC9885860 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

Casadó-Anguera Verònica V Moreno Estefanía E Sánchez-Soto Marta M Cai Ning Sheng NS Bonaventura Jordi J Homar-Ruano Patricia P Rubinstein Marcelo M Cortés Antoni A Canela Enric I EI Ferré Sergi S Casadó Vicent V

Pharmacological research 20210626

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 D4.7 receptor variant and attention deficit hyperactivity disorder (ADHD). The α2A adrenoceptor gene has also been associated with ADHD. In fact, drugs targeting the α2A adrenoceptor (α2AR), such as guanfacine, are ...[more]

PMID: 34182128

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Heteromerization between α_2A adrenoceptors and different polymorphic variants of the dopamine D₄ receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

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Heteromerization between α<sub>2A</sub> adrenoceptors and different polymorphic variants of the dopamine D<sub>4</sub> receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

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Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

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Heteromerization between α&lt;sub&gt;2A&lt;/sub&gt; adrenoceptors and different polymorphic variants of the dopamine D&lt;sub&gt;4&lt;/sub&gt; receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

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OmicsDI is part of the ELIXIR infrastructure

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Heteromerization between α_2A adrenoceptors and different polymorphic variants of the dopamine D₄ receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.

Heteromerization between α<sub>2A</sub> adrenoceptors and different polymorphic variants of the dopamine D<sub>4</sub> receptor determines pharmacological and functional differences. Implications for impulsive-control disorders.