Endotoxin transduces Ca2+ signaling via platelet-activating factor receptor.
Lipopolysaccharide (LPS) is a pathogenic substance causing severe multiple organ failures and high mortality. Although several LPS binding proteins have been identified, the molecular mechanism underlying the LPS signaling pathway still remains obscure. We have found that the LPS-induced Ca2+ increase in platelets and platelet aggregation is blocked by selective platelet-activating factor (PAF) receptor antagonists, thus suggesting a cross-talk between LPS and the PAF receptor. Next, we confirmed this hypothesis using the cloned PAF receptors [(1991) Nature 349, 342-346; (1991) J. Biol. Chem. 266, 20400-20405] expressed in Xenopus oocytes and Chinese hamster ovary (CHO) cells. In both systems, cells responded to LPS only when PAF receptors were expressed, and specific PAF binding was successfully displaced and reversibly dissociated by LPS. PAF receptor activation by LPS may represent a novel important pathway in the pathogenesis of circulatory collapse and systemic thrombosis caused by endotoxin.
Nakamura
M
M
Department of Biochemistry, Faculty of Medicine, University of Tokyo, Japan.
Honda
Z
Z
Waga
I
I
Matsumoto
T
T
Noma
M
M
Shimizu
T
T
D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D008050:Lipid A / Q000494:pharmacology; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000187:drug effects*; D014981:Xenopus
D018118:Chloride Channels; D002712:Chlorides; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D002118:Calcium