Current perspectives on the selective regulation of dopamine D2 and D3 receptors

Among the characterized dopamine receptor subtypes, D₂ receptor (D₂R) and D₃ receptor (D₃R) are the main targets of neuroleptics that are currently in use. In particular, D₃R is closely related to the etiology of schizophrenia and drug addiction. The spatial expression patterns of D₂R and D₃R are distinct in certain areas of the brain. D₂R are heavily expressed in the regions responsible for motor functions, whereas D₃R are more selectively expressed in the limbic regions, which are associated with cognitive and emotional functions. Therefore, disturbances in the motor and endocrine functions, which are the most serious problems caused by the current neuroleptics, are likely to result from the non-selective blockade of D₂R. Selective regulation of D₃R is needed to separate the desired therapeutic activities from unwanted side effects that result from promiscuous blockade of other receptors. D₂R and D₃R possess high sequence homology and employ similar signaling pathways, and it is difficult to selectively regulate them. In this review, we discuss the signaling mechanisms, intracellular trafficking, and desensitization properties of D₂R and D₃R. In addition, the proteins interacting with D₂R or D³R are discussed in relation to their roles in the regulation of receptor functions, followed by the current status of the development of selective D₃R ligands.