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 DRD 1 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 D 1 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 DRD 1 group the monophyly of each paralog was recovered with strong support, and phylogenetic relationships among them were well resolved. Within the DRD 1 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 DRD 1 clade was recovered sister to the aforementioned clade, and the group containing DRD 5 receptors was sister to all other DRD 1 paralogs. In agreement with the literature, among the DRD 2 class of receptors, DRD 2 was recovered sister to DRD 3 , whereas DRD 4 was sister to the DRD 2 /DRD 3 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.