Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

被引：55

作者：

Parcq, J. ^{[1
]}

Bertrand, T. ^{[1
]}

Montagne, A. ^{[1
]}

Baron, A. F. ^{[1
]}

Macrez, R. ^{[1
]}

Billard, J. M. ^{[2
]}

Briens, A. ^{[1
]}

Hommet, Y. ^{[1
]}

Wu, J. ^{[3
]}

Yepes, M. ^{[3
]}

Lijnen, H. R. ^{[4
]}

Dutar, P. ^{[2
]}

Angles-Cano, E. ^{[1
]}

Vivien, D. ^{[1
]}

机构：

[1] Univ Caen Basse Normandie, Serine Proteases & Pathophysiol Neurovasc Unit, Inserm U919, GIP Cyceron, F-14000 Caen, France

[2] Univ Paris 05, Ctr Psychiat & Neurosci, Inserm U894, Paris, France

[3] Emory Univ, Sch Med, Dept Neurol, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA

[4] Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Louvain, Belgium

来源：

CELL DEATH AND DIFFERENTIATION | 2012年 / 19卷 / 12期

基金：

美国国家卫生研究院;

关键词：

tissue plasminogen activator; protease; zymogen; neurotoxicity; long-term potentiation; TISSUE-PLASMINOGEN-ACTIVATOR; LONG-TERM POTENTIATION; NEURONAL DEGENERATION; LATE-PHASE; NEUROSERPIN; SEIZURE; FIBRIN; GENE; INHIBITION; EXPRESSION;

D O I：

10.1038/cdd.2012.86

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(1/2) 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. Cell Death and Differentiation (2012) 19, 1983-1991; doi:10.1038/cdd.2012.86; published online 29 June 2012

引用

页码：1983 / 1991

页数：9

共 40 条

[11]

HALL SW, 1991, J BIOL CHEM, V266, P12329

[12] The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity [J].

Harston, George W. J. ;

Sutherland, Brad A. ;

Kennedy, James ;

Buchan, Alastair M. .

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2010, 30 (11) :1804-1816

[13] Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways [J].

Huang, YY ;

Bach, ME ;

Lipp, HP ;

Zhuo, M ;

Wolfer, DP ;

Hawkins, RD ;

Schoonjans, L ;

Kandel, ER ;

Godfraind, JM ;

Mulligan, R ;

Collen, D ;

Carmeliet, P .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (16) :8699-8704

[14] Non-proteolytic neurotrophic effects of tissue plasminogen activator on cultured mouse cerebrocortical neurons [J].

Lee, Hee-Young ;

Hwang, Ih-Yeon ;

Im, Hana ;

Koh, Jae-Young ;

Kim, Yang-Hee .

JOURNAL OF NEUROCHEMISTRY, 2007, 101 (05) :1236-1247

[15] Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity [J].

Lopez-Atalaya, Jose P. ;

Roussel, Benoit D. ;

Levrat, Denis ;

Parcq, Jerome ;

Nicole, Olivier ;

Hommet, Yannick ;

Benchenane, Karim ;

Castel, Herve ;

Leprince, Jerome ;

Van, Denis To ;

Bureau, Ronan ;

Rault, Sylvain ;

Vaudry, Hubert ;

Petersen, Karl-Uwe ;

Santos, Jana Sopkova-de Oliveira ;

Ali, Carine ;

Vivien, Denis .

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2008, 28 (06) :1212-1221

[16] Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice [J].

Madani, R ;

Hulo, S ;

Toni, N ;

Madani, H ;

Steimer, T ;

Muller, D ;

Vassalli, JD .

EMBO JOURNAL, 1999, 18 (11) :3007-3012

[17] Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1 [J].

Mannaioni, Guido ;

Orr, Anna G. ;

Hamill, Cecily E. ;

Yuan, Hongjie ;

Pedone, Katherine H. ;

Mccoy, Kelly L. ;

Palmini, Rolando Berlinguer ;

Junge, Candice E. ;

Lee, C. Justin ;

Yepes, Manuel ;

Hepler, John R. ;

Traynelis, Stephen F. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (29) :20600-20611

[18] Tissue plasminogen activator and NMDA receptor cleavage [J].

Matys, T ;

Strickland, S .

NATURE MEDICINE, 2003, 9 (04) :371-372

[19] Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation [J].

Medina, MG ;

Ledesma, MD ;

Domínguez, JE ;

Medina, M ;

Zafra, D ;

Alameda, F ;

Dotti, CG ;

Navarro, P .

EMBO JOURNAL, 2005, 24 (09) :1706-1716

[20] The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling [J].

Nicole, O ;

Docagne, F ;

Ali, C ;

Margaill, I ;

Carmeliet, P ;

MacKenzie, ET ;

Vivien, D ;

Buisson, A .

NATURE MEDICINE, 2001, 7 (01) :59-64

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