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


CONCLUSIONS
Altogether, these results demonstrate a new function for tPA in the central nervous system, which most likely contributes to its pleiotropic functions.
Baron
Amandine
A
INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Cyceron, Caen Cedex F-14074, France.
Hommet
Yannick
Y
Cassé
Frédéric
F
Vivien
Denis
D
D000818:Animals; D005341:Fibrinolysin / Q000378:metabolism*; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin