Endothelin 3

Endothelin-3 is a member of the endothelin family. The endothelin family consists of highly potent vasoconstrictive peptides. Three endogenous isoforms are known - ET-1, ET-2 and ET-3. Due to their physiological role as vasoactive peptides, endothelins are associated with certain cardiovascular and renal diseases; endothelin antagonists could therefore play an important role in the treatment of these diseases. Two different endothelin receptors have been cloned in mammals, classified as ETA and ETB receptors. Endothelin-3 is a protein that in humans is encoded by the EDN3 gene. Four alternatively spliced transcript variants encoding three different isoforms are observed.

Endothelins are endothelium-derived vasoactive peptides that are involved in a variety of biological functions. The active form of this protein is a 21 amino acid peptide that is processed from the precursor protein. The active peptide is a ligand for the endothelin receptor type B (EDNRB). The endothelin system is a vertebrate-specific innovation that plays an important role in the regulation of the cardiovascular system and renal and pulmonary processes, as well as in the development of the vertebrate-specific neural crest cell population and its derivatives (Lahav R et al. 1996). This system consists of three structurally similar peptides of 21 amino acids that bind and activate two G-protein-coupled receptors. Knockouts of the EDN3 and EDNRB genes have demonstrated their crucial function during the development of the enteric nervous system and melanocytes, two derivatives of the neural crest (Bondurand N et al. 2018).

Mutations in the EDN3 gene and EDNRB have been associated with Hirschsprung disease (HSCR) and Waardenburg syndrome (WS), which are congenital disorders involving cells from the neural crest.

1. Bolk S et al (1996). Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nat Genet 13: 395-396.
2. Bondurand N et al. (2018) News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. Dev Biol 444 Suppl 1:156-169.
3. Bourgeois C et al (1997). Endothelin-1 and ETA receptor expression in vascular smooth muscle cells from human placenta: a new ETA receptor messenger ribonucleic acid is generated by alternative splicing of exon 3. J Clin Endocrinol Metab 82: 3116-3123.
4. Hutchins EJ et al. (2018) Migration and diversification of the vagal neural crest. Dev Biol 444 Suppl 1(Suppl 1):98-109.
5. Lahav R et al (1996). Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc Natl Acad Sci U.S.A. 93: 3892-3897.
6. Nakano A et al (1997). Selective conversion of big endothelins to tracheal smooth muscle-constricting 31-amino acid-length endothelins by chymase from human mast cells. J. Immunol 159: 1987-1892.