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Author Notes:

Correspondence: Manuel Yepes, Department of Neurology and Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 615 Michael Street, Suite 505J, Atlanta, Georgia 30322; Telephone: (404) 712 8358; Fax: (404) 727 3728; Email: myepes@emory.edu


Research Funding:

This work was supported in part by National Institutes of Health Grants NS-062073 and P30NS055077 and VA MERIT Award BX000474


  • Excitotoxicity
  • neuroprotection
  • plasminogen
  • tissue-type plasminogen activator

Tissue-type Plasminogen Activator Protects Neurons from Excitotoxin-induced Cell Death via Activation of the ERK 1/2 -CREB-ATF3 Signaling Pathway


Journal Title:

Molecular and Cellular Neuroscience


Volume 52


, Pages 9-19

Type of Work:

Article | Post-print: After Peer Review


The release of the serine proteinase tissue-type plasminogen activator (tPA) from cerebral cortical neurons has a neuroprotective effect in the ischemic brain. Because excitotoxicity is a basic mechanism of ischemia-induced cell death here we investigated the effect of tPA on excitotoxin-induced neuronal death. We report that genetic overexpression of neuronal tPA or treatment with recombinant tPA renders neurons resistant to the harmful effects of an excitotoxic injury in vitro and in vivo. We found that at concentrations found in the ischemic brain tPA interacts with synaptic but not extrasynaptic NMDARs. This effect is independent of tPA’s proteolytic properties and leads to a rapid and transient phosphorylation of the extracellular signal regulated kinases 1 / 2 (ERK ½), with ERK ½-mediated activation of the cAMP response element binding protein (CREB) and induction of the neuroprotective CREB-regulated activating transcription factor 3 (Atf3). In line with these observations, Atf3 down-regulation abrogates the protective effect of tPA against excitotoxin-induced neuronal death. Our data indicate that tPA preferentially activates synaptic NMDARs via a plasminogen-independent mechanism turning on a cell signaling pathway that protects neurons from the deleterious effects of excitotoxicity.

Copyright information:

Published by Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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