EDN3s

Endothelin-3 (ET-3) is a peptide in the endothelin family that participates in vascular regulation and the development of neural crest–derived tissues. The term EDN3s can refer to the EDN3 gene and its encoded mature peptide, as well as orthologous sequences found in different vertebrate species. EDN3 is produced as a prepropeptide that is processed through intermediate forms to the active endothelin-3 peptide, which is a 21‑amino‑acid, disulfide-ring peptide.

Biogenesis and signaling pathways involve proteolytic processing by endothelin‑converting enzymes to generate mature ET‑3. The active peptide signals through endothelin receptors, primarily the G protein–coupled ET_A (EDNRA) and ET_B (EDNRB) receptors. Receptor activation triggers intracellular calcium mobilization and various downstream pathways that regulate vascular tone and smooth muscle contraction; ET_B also participates in peptide clearance and, in some contexts, vasodilation through endothelium‑derived mediators.

Biological roles of EDN3 are broad but especially notable in the development and function of neural crest–derived lineages. ET‑3 signaling influences the migration and differentiation of enteric neurons and contributes to melanocyte development, affecting pigmentation and skin/eye coloration. In addition to developmental roles, EDN3 signaling continues to have tissue‑specific effects in adults, particularly where neural crest–derived cells or endothelin pathways are involved.

Clinical significance is associated with disruptions of EDN3 signaling. Mutations or defects in EDN3 or in the EDNRB receptor can contribute to Hirschsprung disease (congenital aganglionic megacolon) and Waardenburg syndrome type 4, reflecting impaired enteric nervous system development and pigment cell formation.

Evolutionarily, EDN3 and its receptors are conserved across vertebrates, with orthologs showing preserved functional motifs. Expression patterns vary by tissue and developmental stage, consistent with roles in vascular biology and neural crest–derived tissues.