Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determines pharmacological and functional differences. Implications for impulsive-control disorders
| Autor: | Patricia Homar-Ruano, Antoni Cortés, Vicent Casadó, Estefanía Moreno, Jordi Bonaventura, Verònica Casadó-Anguera, Enric I. Canela, Sergi Ferré, Marcelo Rubinstein, Ning Sheng Cai, Marta Sánchez-Soto |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Receptors adrenèrgics Dopamine Population Heteromer Mice Transgenic Dopamina Biology Ligands Article Adrenaline receptors 03 medical and health sciences Mice 0302 clinical medicine Receptors Adrenergic alpha-2 medicine Attention deficit hyperactivity disorder Animals Humans Receptor education Sheep Domestic G protein-coupled receptor Pharmacology Catecholaminergic Cerebral Cortex education.field_of_study Polymorphism Genetic Receptors Dopamine D4 Cerebral cortex medicine.disease Guanfacine Mice Inbred C57BL Escorça cerebral 030104 developmental biology HEK293 Cells Attention Deficit Disorder with Hyperactivity 030220 oncology & carcinogenesis Dopamine Agonists Impulsive Behavior Trastorns per dèficit d'atenció amb hiperactivitat en els adults Attention deficit disorder with hyperactivity in adults Female Neuroscience medicine.drug Protein Binding Signal Transduction |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Pharmacol Res |
| Popis: | Polymorphic alleles of the human dopamine D(4) 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(2A)R), such as guanfacine, are commonly used in ADHD treatment. In view of the involvement of dopamine D(4) receptor (D(4)R) and α(2A)R in ADHD and impulsivity, their concurrent localization in cortical pyramidal neurons and the demonstrated ability of D(4)R to form functional heteromers with other G protein-coupled receptors, in this study we evaluate whether the α(2A)R forms functional heteromers with D(4)R and weather these heteromers show different properties depending on the D(4)R variant involved. Using cortical brain slices from hD(4.7)R knock-in and wild-type mice, here, we demonstrate that α(2A)R and D(4)R heteromerize and constitute a significant functional population of cortical α(2A)R and D(4)R. Moreover, in cortical slices from wild-type mice and in cells transfected with α(2A)R and D(4.4)R, we detect a negative crosstalk within the heteromer. This negative crosstalk is lost in cortex from hD(4.7)R knock-in mice and in cells expressing the D(4.7)R polymorphic variant. We also show a lack of efficacy of D(4)R ligands to promote G protein activation and signaling only within the α(2A)R-D(4.7)R heteromer. Taken together, our results suggest that α(2A)R-D(4)R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy. |
| Databáze: | OpenAIRE |
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