Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Proteins interacting with the third cytoplasmic loop of dopamine D₂ and D₃ receptors

Among the various dopamine receptors, D₂-like receptors (D2R, D3R, and D4R) are characterized by a large third cytoplasmic loop, a short carboxyl-terminal tail, and the ability to activate inhibitory G proteins. The diverse activities of D₂-like receptors are partly mediated by proteins that interact with the third cytoplasmic loop, which regulate receptor signaling, receptor trafficking, and stability. Furthermore, in the case of D2R and D3R genes, mRNA splicing generates isoforms in the region of the third cytoplasmic loop. The gene encoding D2R gives rise to two isoforms, termed the dopamine D₂ receptor long isoform (D2LR) and the dopamine D₂ receptor short isoform (D2SR), which lacks 29 amino acids of the D2LR within the third cytoplasmic loop. The D3R gene also produces at least seven distinct alternative splicing variants including D3nf, in which 98 base pairs in the carboxyl-terminal region of the third intracellular loop are deleted. In this review, we focus on proteins interacting with the dopamine D₂/D₃ receptors in the third cytoplasmic loop. We also define a novel binding protein, heart-type fatty acid-binding protein (HFABP), which specifically interacts with the 29 D2LR amino acids deleted in D2SR and document its function in D2LR signaling.