The receptors of the dopamine neurotransmitter belong to two unrelated classes named D-1 and D-2. For the D-1 receptor class, only two subtypes are found in mammals, the D-1A and D-1B,D- receptors, whereas additional subtypes, named D-1C, D-1D, and D-1X, have been found in other vertebrate species. Here, we analyzed molecular phylogeny, gene synteny, and gene expression pattern of the D-1 receptor subtypes in a large range of vertebrate species, which leads us to propose a new view of the evolution of D-1 dopamine receptor genes. First, we show that D-1C and D-1D receptor sequences are encoded by orthologous genes. Second, the previously identified Cypriniform D-1X sequence is a teleost-specific paralog of the D-1B sequences found in all groups of jawed vertebrates. Third, zebrafish and several sauropsid species possess an additional D-1-like gene, which is likely to form another orthology group of vertebrate ancestral genes, which we propose to name D-1E. Ancestral jawed vertebrates are thus likely to have possessed four classes of D-1 receptor genes-D-1A, D-1B(X), D-1C(D), and D-1E-which arose from large-scale gene duplications. The D-1C receptor gene would have been secondarily lost in the mammalian lineage, whereas the D-1E receptor gene would have been lost independently in several lineages of modern vertebrates. The D-1A receptors are well conserved throughout jawed vertebrates, whereas sauropsid D-1C receptors have rapidly diverged, to the point that they were misidentified as D-1D. The functional significance of the D-1C receptor loss is not known. It is possible that the function may have been substituted with D-1A or D-1B receptors in mammals, following the disappearance of D-1C receptors in these species.
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