A new study has discovered complexes of dopaminergic and noradrenergic receptors that could be a therapeutic target to treat attention deficit hyperactivity disorder (ADHD) and impulsivity.

The findings are published in an article titled,”Heteromerization between α2A adrenoceptors and different polymorphic variants of the dopamine D4 receptor determine pharmacological and functional differences. Implications for impulsive-control disorders” in the journal Pharmacological Research, this week.

Vicent Casadó, Estefanía Moreno and Verònica Casadó-Anguera, from the Research Group on Molecular Neuropharmacology. [University of Barcelona]

Dopaminergic and noradrenergic receptors belong to the family of receptors called G-protein coupled receptors (GPCRs)—a  large group of evolutionarily-related cell surface proteins that span the cell’s membrane seven times and sense the presence of molecules outside the cell to trigger specific cellular responses.

“The paper describes for the first time a new heteromer between GPCR receptors and presents innovative results of great interest in neuropharmacology. This line of work could help redirect the focus of the design of new pharmacological treatments to treat neuropsychiatric disorders related to impulsivity and ADHD involving two members of this family: α2AR and D4R receptors”, says Estefanía Moreno, a co-author on the paper and a scientist at the University of Barcelona.

Earlier studies have associated alterations in the type 4 dopamine receptors (D4R) with personality traits and neuropsychiatric disorders. The D4.7 dopamine receptor variant has been linked to ADHD and substance use disorders (SUD).

Expression of the α2A adrenoceptor (α2AR) has also been linked ADHD. Psychostimulants such as methylphenidate or guanfacine, used to treat ADHD target α2ARs. Both D4R and α2AR affect ADHD and impulsivity and are found in pyramidal neurons of the prefrontal cortex.

Since both D4R and α2AR are found in the same neurons, are implicated in the same disorders and D4R is known to form functional complexes (heteromers) with G protein coupled receptors, the researchers in the current study hypothesized that α2AR forms heteromers with D4R that exhibit different properties depending on the D4R variant involved. Their experiments confirm this hypothesis.

“Our results suggest that α2AR-D4R heteromers play a pivotal role in catecholaminergic signaling in the brain cortex and are likely targets for ADHD pharmacotherapy,” the authors note.

In transfected cells and cortical brain slices from mice expressing the human D4.7 receptor, the researchers show α2AR and D4R form heteromers and that these constitute a significant functional population of cortical α2AR and D4R. The study further explores the potential of this heteromer as a target to develop new therapeutical strategies that tackle the treatment for ADHD and impulsivity.

“We show that α2AR receptors can form oligomeric complexes with the most common polymorphism from the D4R receptor (D4.4R) and with the least common polymorphism (D4.7R), which has been correlated to the manifestation of ADHD”, says Verònica Casadó-Anguera, PhD, first author of the article and researcher at the University of Barcelona.

The authors also reveal differences in affinity and signaling depending on the specific variant of the D4 receptor of dopamine that forms the heteromer with the α2A receptors. For instance, they show in α2AR-D4.4R heteromer, both receptors can be activated through the catecholamines, dopamine and norepinephrine but in the α2AR-D4.7R heteromer, the D4.7R receptor can neither be activated by these catecholamines nor by exogenous D4R ligands.

“The negative interaction we described between both receptors within the α2AR-D4.4R heteromer disappears when the D4.7R variant related to ADHD is involved,” says Anguera, “or when we disrupt the formation of heteromers with peptides from the transmembrane domain of the receptors involved in their interaction. This confirms the specificity of the observed effects”.

The α2AR-D4R heteromer acts as a sensor for variations in the concentration of endogenous catecholamines, the authors note.

“The negative interaction that is established physiologically between these two receptors—with a decisive role in controlling impulsivity and attention— does not occur when the individual expresses the ‘abnormal’ D4.7R polymorphism. This variant, which can also be associated with the α2AR adrenergic receptor, acts as a simple ‘stone guest’, but is unable to regulate it, a condition that leads to an excess of impulsivity,” says Vicent Casadó, senior author on the study and scientist at the Department of Biochemistry and Molecular Biomedicine, University of Barcelona.

Nearly half of all new drug development efforts involve members of the G-protein coupled receptors (GPCR) family but the therapeutic success of these drugs is not optimal.

“This is explained by the fact that most current strategies for drug development consider GPCRs as monomeric entities and do not take into account that GPCRs can be associated in heteromeric complexes,” says Casadó.

The results of the current study point out that targeting monomers would be affecting a component that is not always pharmacologically and functionally equivalent to the actual target, which are GPCR oligomers—a complex of two or more units.

Led by scientists in the Group on Molecular Neuropharmacology at the University of Barcelona, collaborating scientists from the National Institute on Drug Abuse of the National Institutes of Health (NIH), the United States and the Institute of Investigation in Genetic engineering and Molecular Biology, Argentina, also participated in the study.

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