Characterizing the binding of dopamine D1–D2 receptors in vitro and in temporal and frontal lobe tissue total protein

Abstract

Dysfunction of the dopaminergic pathway is linked to numerous diseases of the nervous system. The D1–D2 receptor heteromer is known to play a role in certain neuropsychiatric disorders, such as depression. Here, we synthesized an eight amino acid residue peptide, EAARRAQE, derived from the third intracellular loop of the D2 receptor and show that the peptide binds to the D1 receptor with comparable efficiency as that of the full‐length D2 receptor protein. Moreover, immunoprecipitation studies show the existence of a heteromeric complex formed both in vitro and in total protein derived from temporal and frontal lobe tissue from normal and depressed subjects. The efficiency of the peptide to block the D1–D2 heteromeric complex was comparable in all the samples tested.

Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders

“…Furthermore, in support of the potential therapeutic approach of using D1R-D2R heterodimer disruption for treating depressive/anxiety disorders, it was also reported [ 184 ] that prior i.c.v administration of this peptide prevented the depressive/anxiogenic effects that are observed following the SKF83859-mediated D1R-D2R heterodimer formation [ 184 ]. In agreement with the above, EAARRAQE, an eight amino acid peptide derived from the third intracellular loop of the D2 receptor, has also been shown to block to the same extent the formation of D1R-D2R heterodimer both in vitro and in the temporal and in the frontal lobe tissue total protein, suggesting that no adapter/scaffolding proteins are needed for the formation of this receptor heterodimer [ 174 ]. Finally, as a corollary for the development of a successfully preclinical pharmacological treatment, a proper administration route for the recommended medications also needs to be considered.…”

“…D1R-D2R heteromers are predominantly elevated within the nucleus accumbens in comparison with the dorsal striatum, but they have also been described within the medial prefrontal cortex and amygdala [ 173 ]. They have also been demonstrated in samples of total protein derived from the cerebral cortex of normal and depressed individuals [ 174 ]. It should be noted that in a study examining the role of single nucleotide polymorphisms as a risk factor for depression in a population of young (7–18 year-olds) Costa Rican individuals, a significant interaction effect was found between rs1039089 and rs877138 located upstream of the DA D1 and the D2R, respectively.…”