preproendothelin3

Preproendothelin-3 is the precursor protein that gives rise to endothelin-3, a peptide involved in vascular regulation and neural crest-derived development. It is encoded by the EDN3 gene and belongs to the endothelin family. The preproprotein contains an N-terminal signal peptide that directs secretion, followed by a propeptide region.

Processing of preproendothelin-3 involves several proteolytic steps. The signal peptide is removed to form proendothelin-3, which is then cleaved by furin-like convertases to produce big endothelin-3. Endothelin-converting enzymes, such as ECE-1 and ECE-2, further process big ET-3 to generate the mature endothelin-3 peptide, a 21-amino-acid cyclic peptide stabilized by a disulfide bond.

The mature endothelin-3 peptide exerts its effects primarily by binding to endothelin receptors ETA and ETB. Its activity is context-dependent, with notable roles in neural crest-derived tissues and the enteric nervous system, as well as involvement in the regulation of vascular tone in certain vascular beds. Expression of endothelin-3 can be found in various tissues, including the brain, heart, and endothelium, reflecting its diverse functions.

Clinical relevance of the EDN3/endothelin-3 axis is most established in developmental disorders. Mutations or dysregulation of EDN3 or its receptor EDNRB can contribute to Hirschsprung disease, a congenital condition characterized by missing enteric neurons in parts of the intestine. Alterations in endothelin signaling have also been investigated in cardiovascular and cancer biology, highlighting the broader significance of the endothelin pathway.