title: NAADP links histamine H1 receptors to secretion of von Willebrand factor in human endothelial cells.
abstract: A variety of endothelial agonist-induced responses are mediated by rises in intracellular Ca(2+), suggesting that different Ca(2+) signatures could fine-tune specific inflammatory and thrombotic activities. In search of new intracellular mechanisms modulating endothelial effector functions, we identified nicotinic acid adenine dinucleotide phosphate (NAADP) as a crucial second messenger in histamine-induced Ca(2+) release via H1 receptors (H1R). NAADP is a potent intracellular messenger mobilizing Ca(2+) from lysosome-like acidic compartments, functionally coupled to the endoplasmic reticulum. Using the human EA.hy926 endothelial cell line and primary human umbilical vein endothelial cells, we show that selective H1R activation increases intracellular NAADP levels and that H1R-induced calcium release involves both acidic organelles and the endoplasmic reticulum. To assess that NAADP links H1R to Ca(2+)-signaling we used both microinjection of self-inactivating concentrations of NAADP and the specific NAADP receptor antagonist, Ned-19, both of which completely abolished H1R-induced but not thrombin-induced Ca(2+) mobilization. Interestingly, H1R-mediated von Willebrand factor (VWF) secretion was completely inhibited by treatment with Ned-19 and by siRNA knockdown of 2-pore channel NAADP receptors, whereas thrombin-induced VWF secretion failed to be affected. These findings demonstrate a novel and specific Ca(2+)-signaling mechanism activated through H1R in human endothelial cells, which reveals an obligatory role of NAADP in the control of VWF secretion.
authors.affiliation: Department of Anatomy, Sapienza University of Rome, Rome, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Esposito
authors.forename: Guido
authors.initials: G
authors.lastname: Gambara
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lewis
authors.forename: Fioretta
authors.initials: F
authors.lastname: Palombi
authors.forename: Alessio
authors.initials: A
authors.lastname: D'Alessio
authors.forename: Lewis X
authors.initials: LX
authors.lastname: Taylor
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Elio
authors.initials: E
authors.lastname: Ziparo
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.forename: Antonio
authors.initials: A
authors.lastname: Filippini
mesh_terms: D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006538:Heptanoic Acids / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism*; D000097903:Two-Pore Channels
chemical_list: D015220:Calcium Channels; D002243:Carbolines; D006538:Heptanoic Acids; D006632:Histamine; D009249:NADP; D018733:Nicotinic Antagonists; D010879:Piperazines; D010880:Piperidines; D034741:RNA, Small Interfering; D011969:Receptors, Histamine H1; D014841:von Willebrand Factor; C539827:1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid; C501946:2,2,6,6-tetramethylpiperidin-4-yl heptanoate; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C530224:TPCN2 protein, human; C024376:NAADP