Upon Edn ligand binding endothelin receptors
Upon Edn ligand binding, endothelin receptors can induce a variety of intracellular signaling cascades leading to diverse cellular responses such as contraction in the case of smooth muscle cells, or cell growth and mitogenesis. Ednrs are expressed in a variety of cell types and tissues, for example in endothelial and smooth muscle cells, cardiomyocytes of the heart, in the central and enteric nervous system, and in pigment cells, where they exert their multiple physiological and developmental roles (Khimji and Rockey, 2010, Rubanyi and Polokoff, 1994, Schneider et al., 2007).
The importance of endothelin signaling in multiple diseases has lead to the advancement of pharmacological strategies to interfere with the endothelin axis. A growing number of endothelin antagonists, that for example competitively inhibit the binding of endothelin ligands to the receptors, are available for the treatment of specific types of diseases and cancers (for reviews, see e.g., Bagnato et al., 2011, Battistini et al., 2006, Motte et al., 2006).
Almost 25,000 articles on the endothelin system have been published in the 25years since its discovery, but studies that address the evolution and function of the endothelin system outside mammals are still comparatively scarce. While the human genome encodes three endothelin ligands (EDN1, EDN2, and EDN3) and two endothelin receptors (EDNRA and EDNRB), recent analyses from a variety of vertebrate lineages highlighted the XMU-MP-1 and of the vertebrate endothelin system with up to seven ligand genes in lampreys (Kuraku et al., 2010) and five endothelin receptors in teleost fish (Braasch et al., 2009, Hyndman et al., 2009). Here we review recent advances in our understanding on the evolution of the endothelin GPCR gene family and their ligands, complemented by the analysis of Ednr gene repertoires in new genome assemblies from phylogenetically informative taxa such as amphioxus, lampreys, and cartilaginous, ray-finned, and lobe-finned fish.
Evolutionary origins of the endothelin system
Evolution of vertebrate endothelin receptors Phylogenetic analyses of Ednr proteins from 30 species covering all major vertebrate lineages are shown in Fig. 3 and Supplementary Fig. S2; accession numbers and genomic locations are listed in Supplementary Table 1. Below, we will discuss the distribution of endothelin receptor genes among vertebrates in the light of newly available genome assemblies from species covering phylogenetically particularly informative branches of the vertebrate radiation.
Relationship of endothelin receptors: an evolutionary model A model for the evolution of endothelin receptors in chordates is shown in Fig. 7. Following the two rounds of whole genome duplication at the base of the vertebrate lineage, VGD1 and VGD2, initially four Ednr genes were present in vertebrates. The amplification of Ednr genes by the course of VGD1/2 is supported by the fact that the three Ednr gene regions in gnathostome genomes share conserved synteny with each other, including paralogs of other gene families such as Pou4f, Spry, Slain genes (Figs. 4B and 5), and the Parahox paralogon gene members (Braasch et al., 2009, Fredriksson et al., 2003). According to this model, the fourth Ednr ohnolog would have been lost right after VGD1/2. In the human genome, based on the location of the Parahox paralogons and other Ednr neighboring gene families, one would predict that the fourth Ednr gene became lost from a region now located on chromosome Hsa5 (Figs. 2 and 4B), while EdnrB2 was most probably lost from HsaX/Y as mentioned above (Braasch et al., 2009). Kuraku et al. (2010) presented phylogenetic evidence that the lamprey EdnrA gene is indeed orthologous to the gnathostome EdnrA genes, supporting the view that the duplications of vertebrate Ednr predate the divergences of agnathans and gnathostomes. This is consistent with the conclusion of large-scale phylogenetic analyses of vertebrate gene families including lamprey and hagfish sequences that both vertebrate genome duplications VGD1 and VGD2 predated the divergence of all living vertebrate lineages (Kuraku et al., 2009, Smith et al., 2013). This leads to the parsimonious hypothesis that the fourth Ednr gene was lost before the divergence of agnathans and gnathostomes (Fig. 7 insert, ‘hypothesis A’). An alternative, less parsimonious hypothesis would be that lamprey EdnrA and gnathostome EdnrA are ‘hidden paralogs’ (Kuraku, 2013) and that the fourth Ednr ohnolog was lost independently in jawed and jawless vertebrates (Fig. 7 insert, ‘hypothesis B’). Under this scenario, gnathostome EdnrA would be orthologous to the lost fourth agnathan Ednr ohnolog, and the agnathan EdnrA would then be orthologous to the lost fourth gnathostome Ednr gene.