THE CONTROL OF ENDOTHELIN-1 SECRETION

1. The human endothelin-l (ET-1) gene, which is located on chromosome 6, contains cis-regulatory elements in the 5'-flanking region includin g the TPA-responsive element, nuclear factor 1 binding element and GAT A motif. 2. The expression of preproendothelin-l (PPET-1) mRNA is regu lated by a mechanism involving receptor mediated mobilization of intra cellular Ca2+ and activation of protein kinase C in endothelial cells. 3. Activation of protein kinase C results in the synthesis of c-Jun p rotein and the rapid dephosphorylation of c-Jun protein. Consequently, the binding activity of c-Jun protein to the TPA-responsive element i ncreases, and this causes the induction of PPET-1 mRNA. 4. The microtu bular system seems to play some important roles in ET-1 secretion, esp ecially in the process of transferring the synthesized ET-1 to the cel l surface of the endothelial cells. 5. The secretion of ET-I from endo thelial cells is also regulated by intracellular Ca2+ released from th e Ca2+ store and by Ca2+-calmodulin complex. The phosphorylation of th e myosin light chain, elicited by myosin light chain kinase and activa ted by Ca2+-calmodulin complex, facilitates the formation of filamento us myosin and actin which probably participate in ET-1 secretion espec ially in transporting the ET-l-containing vesicles towards the cell me mbrane in the stimulated endothelial cells. 6. Many cultured cells, ot her than endothelial cells, also secrete ET-1 into the culture medium and this secretion can be stimulated by a variety of agents.