Evolution of endothelin receptors in vertebrates

• 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.

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.