A network map of endothelin mediated signaling pathway

摘要

Endothelins are peptide ligands belonging to the family of 21- amino acid isopeptides. They get primarily secreted by the endothelium and are crucially involved in vasomodulation. There are three types of endothelins, i.e., EDN1 (Endothelin 1), EDN2 (Endothelin 2), and EDN3 (Endothelin 3) encoded by chromosomes 6, 1 and, 20, which are produced by sequential cleavage of the respective endothelin precursors. The endothelins are secreted as an inactive pre-pro-endothelins mainly in vascular endothelial cells, which then undergoes subsequent proteolytic cleavage to produce pro-endothelins. The proteolysis of pro-endothelins into big-endothelins, which in the case of big-EDN1, is carried out by furin-like proteases (Barton and Yanagisawa 2008). The conversion of the inactive precursor peptide, i.e., big-endothelin to the active endothelin, is carried out by endothelin converting enzymes (ECEs) or secreted soluble endopeptidases (Barton et al. 2003). Among the endothelins, EDN1 is the most abundant, primarily secreted by the endothelial cells and other cell types including, airway epithelial cells, macrophages, fibroblasts cardiomyocytes, neurons, and vascular smooth muscle cells (Hynynen and Khalil 2006, Sugo et al. 2001). EDN2 is secreted by ovary, intestinal epithelial cells, whereas EDN3 is expressed in endothelial cells, brain neurons, renal tubular epithelial cells and intestinal epithelial cells (Kedzierski and Yanagisawa 2001, Matsumoto et al. 1989). The endothelins are known to interact with endothelin receptors, i.e., endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB), both of which belong to the family of G proteincoupled receptors (GPCRs). EDNRA shows the highest affinity to EDN1 and EDN2 more than that of EDN3, whereas EDNRB has equal affinities for all endothelin peptides (Barton and Yanagisawa 2008). The distribution pattern of endothelins varies extensively in different organs, which predict their role in both physiological and pathophysiological functions. The endothelin-mediated signaling is reported to differ mainly in normal and pathological conditions (Miyauchi and Goto 1999). The EDNRA receptor is known to mediate cellular proliferation, growth, vasoconstriction and inflammation, resulting in adverse vascular effects. In contrast, the EDNRB receptor is involved in vasodilation and inhibition of growth and inflammation (Luscher and Barton 2000). The opposing roles of ENDRA and EDNRB reiterate their importance in normal and pathophysiological conditions. Thereby it necessitates a better understanding of the cellular response to endothelin receptor signaling.