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Biology of the Cell (2010) 102, (539–547) (Printed in Great Britain)

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Tissue-type plasminogen activator induces plasmin-dependent proteolysis of intracellular neuronal nitric oxide synthase

Amandine Baron*†‡¹, Yannick Hommet*†‡¹, Frédéric Cassé*†‡ and Denis Vivien*†‡²

*INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Cyceron, Caen Cedex F-14074, France, †University of Caen Basse-Normandie, Caen Cedex F-14074, France, and ‡CNRS, UMR CNRS 6232 Ci-NAPs ‘Center for Imaging – Neurosciences and Application to Pathologies’, Cyceron, Caen Cedex F-14074, France

Key words: neuron, neuronal nitric oxide synthase, plasmin, proteolysis, tissue-type plasminogen activator.

Abbreviations used: ε-ACA, ε-amino hexanoic acid; BCA, bicinchoninic acid; DAF-2, 4,5-diaminofluorescein; DIV, days in vitro; DMEM, Dulbecco's modified Eagle's medium; LRP, low-density lipoprotein receptor-related protein; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; PAR-1, plasminogen activating receptor-1; Ptprz, tyrosine phosphatase receptor type Z; RAP, receptor-associated protein; tPA, tissue plasminogen activator; TRAP, thrombin-receptor-activator peptide.

¹These authors contributed equally to this work.

²To whom correspondence should be addressed (email vivien@cyceron.fr).

Background information. Despite its pro-fibrinolytic activity, tPA (tissue plasminogen activator) is a serine protease known to influence a number of physiological and pathological functions in the central nervous system. Accordingly, tPA was reported to mediate some of its functions in the central nervous system through NMDA (N-methyl-D-aspartate) receptors, LRP (low-density lipoprotein receptor-related protein) or annexin II.

Results. We provide here both in vitro and in vivo evidence that tPA could mediate proteolysis and subsequent delocalization of neuronal nitric oxide synthase, thereby reducing endogenous neuronal nitric oxide release. We also demonstrate that although this effect is independent of NMDA receptors, LRP signalling and calpain-mediated proteolysis, it is dependent on the ability of tPA to promote the conversion of plasminogen into plasmin.

Conclusion. Altogether, these results demonstrate a new function for tPA in the central nervous system, which most likely contributes to its pleiotropic functions.

Received 9 June 2010/13 July 2010; accepted 16 July 2010

Published as Immediate Publication 16 July 2010, doi:10.1042/BC20100072

© The Authors Journal compilation © 2010 Portland Press Limited