proendothelin3

Proendothelin-3 is the precursor form of endothelin-3 (ET-3) and is encoded by the EDN3 gene in humans. It is synthesized as part of a larger prepropeptide containing a signal sequence that targets it to the secretory pathway. Removal of the signal peptide yields the proendothelin-3 intermediate, which is subsequently cleaved by endothelin-converting enzymes to generate the mature, active endothelin-3 peptide.

Endothelin-3 belongs to the endothelin family, which also includes endothelin-1 and endothelin-2. ET-3 is a potent vasoactive peptide that contributes to vasoconstriction and regulation of smooth muscle tone. Its biological effects are mediated by binding to endothelin receptors, principally the endothelin receptor type B (ETB), with the possibility of interaction with ETA to a lesser extent. In developmental contexts, ET-3 signaling through EDNRB is important for the migration and differentiation of neural crest–derived cells, particularly enteric neurons.

Expression patterns of EDN3 are prominent in neural crest–derived tissues during development and in certain tissues such as the gut and specific brain regions, with expression persisting in some adult tissues. The ET-3/EDNRB signaling axis plays a critical role in enteric nervous system formation and pigmentation pathways.

Clinical significance arises from disruptions in EDN3 or EDNRB signaling, which have been associated with Hirschsprung disease, a congenital disorder characterized by aganglionosis of the distal bowel. Variants affecting EDN3 or its receptor can contribute to neural crest–related developmental disorders and pigmentary abnormalities.