Heteromerization of dopaminergic receptors in the brain: Pharmacological implications

Dopamine exerts its physiological effects through two subtypes of receptors, i.e. the receptors of the D1 family (D1R and D5R) and the D2 family (D2R, D3R, and D4R), which differ in their pattern of distribution, affinity, and signaling. The D1-like subfamily (D1R and D5R) are coupled to Gαs/olf proteins to activate adenylyl cyclase whereas the D2-like receptors are coupled to Gαi/o subunits and suppress the activity of adenylyl cyclase. Dopamine receptors are capable of forming homodimers, heterodimers, and higher-order oligomeric complexes, resulting in a change in the individual protomers' recognition, signaling, and pharmacology. Heteromerization has the potential to modify the canonical pharmacological features of individual monomeric units such as ligand affinity, activation, signaling, and cellular trafficking through allosteric interactions, reviving the field and introducing a new pharmacological target. Since heteromers are expressed and formed in a tissue-specific manner, they could provide the framework to design selective and effective drug candidates, such as brain-penetrant heterobivalent drugs and interfering peptides, with limited side effects. Therefore, heteromerization could be a promising area of pharmacology research, as it could contribute to the development of novel pharmacological interventions for dopamine dysregulated brain disorders such as addiction, schizophrenia, cognition, Parkinson's disease, and other motor-related disorders. This review is articulated based on the three criteria established by the International Union of Basic and Clinical Pharmacology for GPCR heterodimers (IUPHAR): evidence of co-localization and physical interactions in native or primary tissue, presence of a new physiological and functional property than the individual protomers, and loss of interaction and functional fingerprints upon heterodimer disruption.