A study published by the journalPharmacological ResearchThis article describes the existence a complex made up of dopamine receptors and noradrenergic receptors. It could be a therapeutic target for attention deficit hyperactivity disorder (ADHD), and impulsivity.
The paper, a preclinical study, has been carried out by the Research Group on Molecular Neuropharmacology, under the supervision of the lecturer Vicent Casadó, from the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB). The National Institute on Drug Abuse of both the National Institutes of Health of the United States (NIH), as well as the Institute of Investigation in Genetic engineering in Argentina, are other participants.
α2AR-D4R complexes: beyond the monomeric model
The type 4 dopamine-receptor gene (DRD4) has different genetic polymorphisms. These have been linked in the scientific literature with individual differences related personality traits and neuropsychiatric disorder. This study examines the relationship between D4.7 dopamine receptor gene expression and ADHD and substance use disorders (SUD).
The results reveal an association between the gene encoding the α2A adrenoceptor and ADHD. Located in the pyramidal neurons of the prefrontal cortex, the α2A adrenoreceptors (α2AR) are the main pharmacological targets that facilitate the therapeutical effects of psychostimulants ─such as methylphenidate or guanfacine─ used in the treatment for ADHD.
The paper reveals these receptors are able to associate to form α2AR-D4R complexes or heteromers. This hypothesis was confirmed by the results. It was based upon its association with ADHD, impulsivity, and cortical pyramidal neural neurons. Also, it is known that G protein-coupled receptors (GPCR), are able to form functional heteromers.
The study, conducted in transfected cells and in transgenic laboratory animal models that express the human D4.7R receptor, explores the functionality of α2AR-D4R heteromers and its potential interest 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 the researcher Verònica Casadó-Anguera, first author of the article.
The use of catecholamines ─noradrenalin and dopamine, as well as synthetic drugs─ in the research protocol has revealed the existence of differences in the affinity and signalling depending on the variant of the D4 receptor of dopamine that forms the heteromeric complex with the α2A receptors. Regarding the α2AR-D4.4R heteromer, both receptors can activate through dopamine and norepinephrine. However, within the α2AR-D4.7R heteromer, the D4.7R receptor cannot be activated by these catecholaminergic ligands nor D4R exogen 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 ─continues Verónica Casadó-Anguera─ or when we disrupt the formation of heteromers with peptides from the transmembrane domain of the receptors involved in their interaction. This confirms that the observed effects are specific.
The α2AR-D4R heteromer could therefore be considered a molecular device that detects and responds to small variations in the concentration of endogenous catecholamines, the authors note.
“In short, the study shows that 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,” explains Vicent Casadó.
A new perspective for designing future drugs
About 40% of all drugs on the market today target the GPCR family. This family is a key focus in biomedical research as well as new drug development programs.
Despite their high market presence, GPCR-targeted drugs have not had a complete therapeutic success. “We consider that 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 Vicent Casadó.
The monomeric approach, as the authors point out in their paper, would result in a component that is not always functionally and pharmacologically equivalent to the target, which are GPCR Oligomers.
“Therefore, we published the paper in Pharmacological Research The first time that a new heteromer was discovered between GPCR receptors has been published. This research is of great interest to 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,” concludes the expert Estefanía Moreno, member of the Group on Molecular Neuropharmacology of the UB and the IBUB.