Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance

Abstract

The pharmacological modification of dopamine transmission has long been employed as a therapeutic tool in the treatment of many mental health disorders. However, as many of the pharmacotherapies today are not without significant side effects, or they alleviate only a particular subset of symptoms, the identification of novel therapeutic targets is imperative. In light of these challenges, the recognition that dopamine receptors can form heteromers has significantly expanded the range of physiologically relevant signaling complexes as well as potential drug targets. Furthermore, as the physiology and disease relevance of these receptor heteromers is further understood, their ability to exhibit pharmacological and functional properties distinct from their constituent receptors, or modulate the function of endogenous homomeric receptor complexes, may allow for the development of alternate therapeutic strategies and provide new avenues for drug design. In this review, we describe the emerging neurobiology of the known dopamine receptor heteromers, their physiological relevance in brain, and discuss the potential role of these receptor complexes in neuropsychiatric disease. We highlight their value as targets for future drug development and discuss innovative research strategies designed to selectively target these dopamine receptor heteromers in the search for novel and clinically efficacious pharmacotherapies.

Figure 1

Signaling pathways activated by the dopamine D1-D2 receptor heteromer. Activation of the Gq-coupled D1-D2 heteromer results in PLC-dependent intracellular calcium release, the activation of CaMKII, and increased expression of BDNF potentially via phosphorylation of MeCP2. Dopamine D1-D2 heteromer activation can additionally lead to the phosphorylation, and inactivation, of GSK-3. The phosphorylation state of GSK-3 can potentially be regulated by BDNF-induced activation of TrkB and the subsequent phosphorylation and activation of Akt. Akt then phosphorylates GSK-3α, and GSK-3β resulted in their inactivation. β-Arrestin1 may also inhibit GSK-3α and GSK-3β activation. GSK-3α and GSK-3β can also be phosphorylated by PKC. BDNF, brain-derived neurotrophic factor; β-arr1/2, β-arrestin1 or β-arrestin2; CaMKII, calcium calmodulin kinase II; DAR, dopamine receptor; DAG, diacylglycerol; GSK-3, glycogen synthase kinase-3; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; MeCP2; methyl CpG-binding protein 2; mTORC2, mTOR complex 2; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PDK1, phosphoinositide-dependent kinase-1; PLC, phospholipase C; PKC, protein kinase C; TrkB, tropomyosin receptor kinase B.