title: Norepinephrine down-regulates the activity of protein S on endothelial cells.
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.
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors.forename: J G
authors.initials: JG
authors.lastname: Brett
authors.forename: S F
authors.initials: SF
authors.lastname: Steinberg
authors.forename: P G
authors.initials: PG
authors.lastname: deGroot
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D009638:Norepinephrine / Q000494:pharmacology*; D037342:Pertussis Toxin; D010703:Phorbol Esters / Q000494:pharmacology; D017293:Protein S; D012636:Secretory Rate / Q000187:drug effects; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D010703:Phorbol Esters; D017293:Protein S; D010566:Virulence Factors, Bordetella; D014841:von Willebrand Factor; D000246:Adenosine Diphosphate Ribose; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D009638:Norepinephrine