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. 1988 Jun 1;106(6):2109–2118. doi: 10.1083/jcb.106.6.2109

Norepinephrine down-regulates the activity of protein S on endothelial cells

PMCID: PMC2115154  PMID: 2968346

Abstract

The adrenergic agonist norepinephrine is shown to stimulate endothelium to induce protein S release and degradation, leading to diminished anti- coagulant activity and to down-regulation of protein S cell surface- binding sites. Norepinephrine-induced release of intracellular protein S was blocked by the alpha 1-adrenergic antagonist prazosin (10(-7) M) but not by the alpha-adrenergic antagonist propranolol (10(-6) M) or the alpha 2-adrenergic antagonist yohimbine (10(-5) M) indicating that this response resulted from the specific interaction of norepinephrine with a class of alpha 1-adrenergic receptors not previously observed on endothelium. Attenuation of norepinephrine-induced release of protein S by pertussis toxin in association with the ADP-ribosylation of a 41,000- D membrane protein indicates that this intracellular transduction pathway involves a regulatory G protein. The observation that protein S was released from endothelium in response to maneuvers which elevate intracellular calcium or activate protein kinase C suggests that the response may be mediated via intermediates generated through the hydrolysis of phosphoinositides. Morphologic studies were consistent with a mechanism in which norepinephrine causes exocytosis of vesicles containing protein S. In addition to release of protein S, norepinephrine also induced loss of endothelial cell protein S-binding sites, thereby blocking effective activated protein C-protein S- mediated factor Va inactivation on the cell surface. Norepinephrine- mediated endothelial cell stimulation thus results in loss of intracellular protein S and suppression of cell surface-binding sites, modulating the anti-coagulant protein C pathway on the vessel wall. These studies define a new relationship between an anti-coagulant mechanism and the autonomic nervous system, and indicate a potential role for an heretofore unrecognized class of alpha 1-adrenergic receptors in the regulation of endothelial cell physiology.

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Selected References

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