title: Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity.
abstract: Unlike other serine proteases that are zymogens, the single-chain form of tissue plasminogen activator (sc-tPA) exhibits an intrinsic activity similar to that of its cleaved two-chain form (tc-tPA), especially in the presence of fibrin. In the central nervous system tPA controls brain functions and dysfunctions through its proteolytic activity. We demonstrated here, both in vitro and in vivo, that the intrinsic activity of sc-tPA selectively modulates N-methyl-D-aspartate receptor (NMDAR) signaling as compared with tc-tPA. Thus, sc-tPA enhances NMDAR-mediated calcium influx, Erk(½) activation and neurotoxicity in cultured cortical neurons, excitotoxicity in the striatum and NMDAR-dependent long-term potentiation in the hippocampal CA-1 network. As the first demonstration of a differential function for sc-tPA and tc-tPA, this finding opens a new area of investigations on tPA functions in the absence of its allosteric regulator, fibrin.
authors: Inserm U919, Serine Proteases and Pathophysiology of the neurovascular Unit, Université de Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors: J
authors: J
authors: Parcq
authors: T
authors: T
authors: Bertrand
authors: A
authors: A
authors: Montagne
authors: A F
authors: AF
authors: Baron
authors: R
authors: R
authors: Macrez
authors: J M
authors: JM
authors: Billard
authors: A
authors: A
authors: Briens
authors: Y
authors: Y
authors: Hommet
authors: J
authors: J
authors: Wu
authors: M
authors: M
authors: Yepes
authors: H R
authors: HR
authors: Lijnen
authors: P
authors: P
authors: Dutar
authors: E
authors: E
authors: Anglés-Cano
authors: D
authors: D
authors: Vivien
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D016202:N-Methylaspartate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010959:Tissue Plasminogen Activator; D002118:Calcium