title: Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide.
abstract: Nitric oxide (NO) is a ubiquitous, cell-permeable intercellular messenger. The current concept assumes that NO diffuses freely through the plasma membrane into the cytoplasm of a target cell, where it activates its cytosolic receptor enzyme, soluble guanylyl cyclase (sGC). Recent evidence, however, suggests that cellular membranes are not only the predominant site of calcium-dependent NO synthesis, but also the site of its distribution and binding. Here we extend this concept to NO signalling to show that active sGC is partially associated with the plasma membrane in a state of enhanced NO sensitivity. After cellular activation, sGC further translocates to the membrane fraction in human platelets and associates with the NO-synthase-containing caveolar fraction in rat lung endothelial cells, in a manner that is dependent on the concentration of intracellular calcium. Our data suggest that the entire NO signalling pathway is more spatially confined than previously assumed and that sGC dynamically translocates to the plasma membrane, where it is sensitized to NO.
authors.affiliation: Department of Pharmacology and Toxicology, Julius-Maximilians-University, Versbacher Str. 9, 97078 Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zabel
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Phil
authors.initials: P
authors.lastname: Oh
authors.forename: Pavel
authors.initials: P
authors.lastname: Nedvetsky
authors.forename: Albert
authors.initials: A
authors.lastname: Smolenski
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.forename: Petra
authors.initials: P
authors.lastname: Kronich
authors.forename: Peter
authors.initials: P
authors.lastname: Kugler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Jan E
authors.initials: JE
authors.lastname: Schnitzer
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D004727:Endothelium / Q000473:pathology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D002118:Calcium