The control of endothelin-1 secretion.
1. The human endothelin-1 (ET-1) gene, which is located on chromosome 6, contains cis-regulatory elements in the 5'-flanking region including the TPA-responsive element, nuclear factor 1 binding element and GATA motif. 2. The expression of preproendothelin-1 (PPET-1) mRNA is regulated by a mechanism involving receptor mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells. 3. Activation of protein kinase C results in the synthesis of c-Jun protein and the rapid dephosphorylation of c-Jun protein. Consequently, the binding activity of c-Jun protein to the TPA-responsive element increases, and this causes the induction of PPET-1 mRNA. 4. The microtubular system seems to play some important roles in ET-1 secretion, especially in the process of transferring the synthesized ET-1 to the cell surface of the endothelial cells. 5. The secretion of ET-1 from endothelial cells is also regulated by intracellular Ca2+ released from the Ca2+ store and by Ca2+-calmodulin complex. The phosphorylation of the myosin light chain, elicited by myosin light chain kinase and activated by Ca2+-calmodulin complex, facilitates the formation of filamentous myosin and actin which probably participate in ET-1 secretion especially in transporting the ET-1-containing vesicles towards the cell membrane in the stimulated endothelial cells. 6. Many cultured cells, other than endothelial cells, also secret ET-1 into the culture medium and this secretion can be stimulated by a variety of agents.
Tasaka
K
K
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Kitazumi
K
K
D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics* / Q000378:metabolism*; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008870:Microtubules / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011493:Protein Kinase C; D002118:Calcium