Review
Evolution of endothelin receptors in vertebrates

https://doi.org/10.1016/j.ygcen.2014.06.028Get rights and content

Highlights

  • The endothelin signaling system is a vertebrate innovation.

  • New genome assemblies reveal the vertebrate endothelin receptor (Ednr) diversity.

  • Ednrs and their endothelin ligands were amplified by vertebrate genome duplications.

  • The endothelin system has major roles in cardiovascular regulation and neural crest development.

  • Functional studies on non-tetrapod Ednrs are sparse, offering new research avenues.

Abstract

Endothelin receptors are G protein coupled receptors (GPCRs) of the β-group of rhodopsin receptors that bind to endothelin ligands, which are 21 amino acid long peptides derived from longer prepro-endothelin precursors. The most basal Ednr-like GPCR is found outside vertebrates in the cephalochordate amphioxus, but endothelin ligands are only present among vertebrates, including the lineages of jawless vertebrates (lampreys and hagfishes), cartilaginous vertebrates (sharks, rays, and chimaeras), and bony vertebrates (ray-finned fishes and lobe-finned vertebrates including tetrapods). A bona fide endothelin system is thus a vertebrate-specific innovation with important roles for regulating the cardiovascular system, renal and pulmonary processes, as well as for the development of the vertebrate-specific neural crest cell population and its derivatives. Expectedly, dysregulation of endothelin receptors and the endothelin system leads to a multitude of human diseases.

Despite the importance of different types of endothelin receptors for vertebrate development and physiology, current knowledge on endothelin ligand–receptor interactions, on the expression of endothelin receptors and their ligands, and on the functional roles of the endothelin system for embryonic development and in adult vertebrates is very much biased towards amniote vertebrates. Recent analyses from a variety of vertebrate lineages, however, have shown that the endothelin system in lineages such as teleost fish and lampreys is more diverse and is divergent from the mammalian endothelin system. This diversity is mainly based on differential evolution of numerous endothelin system components among vertebrate lineages generated by two rounds of whole genome duplication (three in teleosts) during vertebrate evolution.

Here we review current understanding of the evolutionary history of the endothelin receptor family in vertebrates supplemented with surveys on the endothelin receptor gene complement of newly available genome assemblies from phylogenetically informative taxa. Our assessment further highlights the diversity of the vertebrate endothelin system and calls for detailed functional and pharmacological analyses of the endothelin system beyond tetrapods.

Section snippets

The endothelin system and endothelin receptors

The endothelin system has a multitude of functions in vertebrates. Discovered in the late 1980s, it was first described to control blood pressure levels by vasoconstriction and vasodilation (Arai et al., 1990, Inoue et al., 1989, Masaki, 2004, Sakurai et al., 1990, Yanagisawa et al., 1988). Further on, it was found that the endothelin system functions also in many other aspects of vertebrate physiology and development, such as neurotransmission, wound healing, kidney homeostasis, osmoregulation

Emergence of the endothelin system at the base of vertebrates

When did the endothelin receptors and the endothelin system as a whole emerge during the course of eukaryote evolution? Surprisingly, endothelin peptides can induce chemotactic behavior in the unicellular ciliate Tetrahymena (Kohidai et al., 2001) and muscle contractions in the cnidarian Hydra (Zhang et al., 2001), and endothelin-like immunoreactivity has been observed for mollusks, insects, and the urochordate Ciona intestinalis (Kasuya et al., 1991). These observations suggested that the

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

Evolution of Edn ligand repertoires

Mirabeau and Joly (2013) suggested that endothelin ligand peptides (present in vertebrates) could be related to the chordate gastrin-releasing (GRP) peptides (present in vertebrates and amphioxus) and the CCH-amide-like (CCHa) peptides of protostomes based on the phylogenetic clustering of their receptors and the fact that endothelin, GRP, and CCHa peptides are all encoded at the N terminus of their precursors. As there is, however, no identifiable sequence similarity among these three peptide

Outlook

Although the endothelin system and endothelin receptors have been studied in detail in the last 25 years, a lot of questions remain regarding their functionality, interaction partners, and pharmacology (Watts, 2010). Furthermore, the availability of new genome assemblies from a multitude of vertebrate lineages highlights the diversity of endothelin system components among vertebrates. From an evolutionary point of view, the functional analysis of endothelin receptors from amphioxus, lampreys and

Acknowledgments

We would like to thank João Cardoso and Dan Larhammar for inviting us to contribute to this special issue as well as Julia Ganz and James T. Nichols for fruitful discussions on the endothelin system and John H. Postlethwait for constant support. This work was supported by grant I/84 815 from the Volkswagen Stiftung, Initiative Evolutionsbiologie (to I.B.), the Deutsche Krebshilfe, and the Deutsche Forschungsgemeinschaft (to M.S.).

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