Evolution of dopamine receptors: phylogenetic evidence suggests a later origin of the DRD_2l and DRD_4rs dopamine receptor gene lineages

Dopamine receptors are integral membrane proteins whose endogenous ligand is dopamine. They play a fundamental role in the central nervous system and dysfunction of dopaminergic neurotransmission is responsible for the generation of a variety of neuropsychiatric disorders. From an evolutionary standpoint, phylogenetic relationships among the DRD₁ class of dopamine receptors are still a matter of debate as in the literature different tree topologies have been proposed. In contrast, phylogenetic relationships among the DRD ₂ group of receptors are well understood. Understanding the time of origin of the different dopamine receptors is also an issue that needs further study, especially for the genes that have restricted phyletic distributions (e.g., DRD_2l and DRD_4rs). Thus, the goal of this study was to investigate the evolution of dopamine receptors, with emphasis on shedding light on the phylogenetic relationships among the D₁ class of dopamine receptors and the time of origin of the DRD_2l and DRD_4rs gene lineages. Our results recovered the monophyly of the two groups of dopamine receptors. Within the DRD₁ group the monophyly of each paralog was recovered with strong support, and phylogenetic relationships among them were well resolved. Within the DRD₁ class of dopamine receptors we recovered the sister group relationship between the DRD_1C and DRD_1E, and this clade was recovered sister to a cyclostome sequence. The DRD₁ clade was recovered sister to the aforementioned clade, and the group containing DRD₅ receptors was sister to all other DRD₁ paralogs. In agreement with the literature, among the DRD₂ class of receptors, DRD₂ was recovered sister to DRD₃, whereas DRD₄ was sister to the DRD₂/DRD₃ clade. According to our phylogenetic tree, the DRD_2l and DRD_4rs gene lineages would have originated in the ancestor of gnathostomes between 615 and 473 mya. Conservation of sequences required for dopaminergic neurotransmission and small changes in regulatory regions suggest a functional refinement of the dopaminergic pathways along evolution.