Fig. 3.
Schematic diagram illustrating synthesis of ET peptides and interaction with receptors. ET isoforms are synthesized by a three-step process: Messenger RNA encodes a prepro-peptide that after a proteolytic cleavage initial of the signal peptidase to yield the propeptide is further cleaved by furin to Big ET precursors. Synthesis of ET-1 has been studied in the most detail. Transformation to the mature, biologically active ET-1 is mainly by the action of ECE-1 at pH 7 but also by ECE-2 at pH 5.5 within endothelial cells. On release from endothelial cells, about one in five molecules of Big ET-1 escape conversion but further processing to ET-1 may occur by smooth muscle ECE or via alternative pathways catalyzed by chymase for ET-1. It is inferred that ET-2 from endothelial cells is synthesized by a similar pathway. ET-3 is not released from human endothelial cells but is also synthesized in other cells by ECE-1 with evidence for an additional pathway, KELL. ET-1 is metabolized by NEP to inactive metabolites. ETs mediate their actions via two GPCRs ETA or ETB and the recommended agonists and antagonists that are most widely used are indicated together with ECE inhibitors.