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Endothelin-1 Signaling Pathway

Endothelin-1 (ET-1) together with endothelin-2 (ET-2), and endothelin-3 (ET-3) comprise the endothelin family of 21 amino acid peptides produced in various cells and tissues, especially endothelial and epithelial lineages. These endothelins are derived from three genes. The endothelins are frequently associated with hypertension (vasoconstriction), however they mediate a variety of other effects through two G-protein coupled receptors, ET-A and ET-B. The endothelins are derived from precursor peptides via cleavage by metalloproteases such as endothelin-converting enzymes.

Endothelin-1 is expressed by endothelial cells as a precursor peptide (proET-1) that is first cleaved to bigET-1 and then to the mature 21-amino acid peptide. The conversion of proET-1 to ET-1 may be mediated by the mammalian convertases, dibasic-processing enzyme (furin) or proprotein convertase PC7 (PC7). ET-1 expression in endothelial cells is regulated by complex signals that involve retinoic acid (RA); leptin, prostaglandins, thrombin, TNF-β, IL-1, hypoxia, and nitric oxide (NO). Hypoxia is a potent inducer of ET-1 gene expression in endothelial cells. This mechanism is important during myocardial ischemia.

Endothelin-1 is a key mediator of vascular tone and renal homeostasis through antagonistic vasoactive effects. ET-1 is a vasoconstrictor, but it also induces the production of the potent vasodilator, nitric oxide (NO). Consequently, dysfunctions of ET-1 signaling are associated with cardiovascular, renal and respiratory diseases, such as high blood pressure, atherosclerosis, systemic and pulmonary hypertension.

ET-1 acts through two receptors, ET-A and ET-B. ET-A receptors are coupled to Gq/11, G12/13 and Gi heterotrimer G protein subunits which link to phospholipase C, RhoA-GTPase and adenylyl cyclase (AC) inhibition, respectively. ET-1 binding to ET-A receptors associated with vascular smooth muscle cells leads to cellular contraction (vasoconstriction) and hypertrophy, whereas ET-1 binding to ET-B receptors in endothelial cells initiates a signaling cascade that leads to nitric oxide (NO), endothelial-derived relaxing factor, production. The signaling of NO production through ET-B receptors via G-protein βγ subunit dimer has been linked to Akt phosphorylation of endothelial nitric oxide synthase (eNOS). The G-protein Galpha12 has been linked to increased levels of eNOS. NO inhibits ET-1 at the level of transcription.

References:

Andreeva, A.V. et. al. (2006) Novel mechanisms of G protein-dependent regulation of endothelial nitric-oxide synthase. Mol. Pharmacol. 69, 975-982.
Dulin. N.O. et. al. (2001) Cyclic AMP-independent activation of protein kinase A by vasoactive peptides. J. Biol. Chem. 276, 20827-20830.
Kourembanas, S. et. al. (1993) Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J. Clin. Invest. 92, 99-104.
Schiffrin, E.L. and Touyz, R.M. (1998) Vascular biology of endothelin. J. Cardiovasc. Pharmacol. 32 Suppl 3, S2-13.

Content for this page is provided by Dennis R. Conrad, Ph.D., a Life Science industry consultant with over 25 years of experience in the formulation and optimization of cell culture media. Dr. Conrad's email address is biomediaexpert@earthlink.net