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The control of endothelin-1 secretion
1Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
General Pharmacology
|October 1, 1994
Summary
Endothelin-1 (ET-1) gene expression in endothelial cells is regulated by intracellular calcium and protein kinase C. This pathway influences preproendothelin-1 (PPET-1) mRNA induction and ET-1 secretion via microtubule and actin-myosin systems.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The human endothelin-1 (ET-1) gene is located on chromosome 6 and possesses cis-regulatory elements in its 5'-flanking region.
- Endothelial cell expression of preproendothelin-1 (PPET-1) mRNA is modulated by receptor-mediated intracellular calcium (Ca2+) mobilization and protein kinase C (PKC) activation.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing endothelin-1 (ET-1) gene expression and secretion in endothelial cells.
- To investigate the role of intracellular signaling pathways, including Ca2+ and PKC, in ET-1 production.
- To explore the involvement of the microtubular and actin-myosin cytoskeletal systems in ET-1 secretion.
Main Methods:
- Analysis of cis-regulatory elements in the 5'-flanking region of the ET-1 gene.
- Investigation of signaling pathways involving intracellular Ca2+, protein kinase C, and c-Jun protein.
- Examination of the role of the microtubular system in ET-1 transport.
- Study of Ca2+-calmodulin complex and myosin light chain phosphorylation in ET-1 secretion.
Main Results:
- PKC activation leads to c-Jun protein synthesis and dephosphorylation, enhancing c-Jun binding to the TPA-responsive element and inducing PPET-1 mRNA.
- The microtubular system is crucial for transferring synthesized ET-1 to the endothelial cell surface.
- Intracellular Ca2+ release and Ca2+-calmodulin complex regulate ET-1 secretion.
- Phosphorylation of myosin light chain via myosin light chain kinase facilitates actin-myosin filament formation, aiding ET-1 vesicle transport.
Conclusions:
- ET-1 gene expression and secretion are complex processes regulated by multiple intracellular signaling and cytoskeletal components in endothelial cells.
- The findings highlight the intricate molecular machinery controlling ET-1 release, with implications for understanding its physiological and pathological roles.
- Various cultured cells, beyond endothelial cells, can secrete ET-1, and this process is amenable to stimulation by diverse agents.