Evolution of vertebrate opioid receptors

Abstract

The opioid peptides and receptors have prominent roles in pain transmission and reward mechanisms in mammals. The evolution of the opioid receptors has so far been little studied, with only a few reports on species other than tetrapods. We have investigated species representing a broader range of vertebrates and found that the four opioid receptor types (delta, kappa, mu, and NOP) are present in most of the species. The gene relationships were deduced by using both phylogenetic analyses and chromosomal location relative to 20 neighboring gene families in databases of assembled genomes. The combined results show that the vertebrate opioid receptor gene family arose by quadruplication of a large chromosomal block containing at least 14 other gene families. The quadruplication seems to coincide with, and, therefore, probably resulted from, the two proposed genome duplications in early vertebrate evolution. We conclude that the quartet of opioid receptors was already present at the origin of jawed vertebrates approximately 450 million years ago. A few additional opioid receptor gene duplications have occurred in bony fishes. Interestingly, the ancestral receptor gene duplications coincide with the origin of the four opioid peptide precursor genes. Thus, the complete vertebrate opioid system was already established in the first jawed vertebrates.

Fig. 1.

Quartet-puzzling maximum likelihood tree of the opioid and NPBW receptors with bootstrap values shown in percentage at each node. The tree is color-coded based on the opioid receptor bearing chicken chromosomes (chromosome 20, orange; chromosome 2, green; chromosome 3, yellow; and chromosome 23, blue). The first three letters of the sequences names are abbreviations of the species names and the number represents the chromosome on which the gene is located. In cases where two genes are located on the same chromosome, “a” or “b” has been added to the sequence names to separate them. For the human sequences, the approved HGNC symbol has also been added to the sequence name. An asterisk after the sequence name means that the sequence has been extended after inspection of the database entries as described in Methods. Hsa, Homo sapiens; Mmu, Mus musculus; Cfa, Canis familiaris; Bta, Bos taurus; Mdo, Monodelphis domestica; Gga, Gallus gallus; Xtr, Xenopus tropicalis; Tgr, Taricha granulosa; Dre, Danio rerio; Ola, Oryzias latipes; Gac, Gasterosteus aculeatus; Tni, Tetraodon nigroviridis; Cmi, Callorhinchus milii; Pma, Petromyzon marinus; Bfl, Branchiostoma floridae; Dme, Drosophila melanogaster.

Fig. 2.

The figure shows the analyzed gene families, including the OPR family, and the chromosomal location of the genes they contain. All human gene names in the figure are approved HGNC symbols and the chicken genes have been given the name of their human orthologs. The tables are color-coded based on the chicken chromosomes (chromosome 2, green; chromosome 20, orange; chromosome 23, blue; and chromosome 3, yellow). An asterisk after the family name indicates that the NJ and QP trees display different topologies (see Figs. S1–S15). The gene family abbreviations are explained in Figs. S2–S15 along with brief descriptions of their properties.

Fig. 3.

Proposed opioid receptor evolution. The opioid and NPBW receptors are shown together with three other gene families that have maintained all four copies after the two tetraploidizations. The BLK and STMN4 genes have been translocated to chromosome 8 in human and the NPBWR2 gene has been lost in chicken.