Ethanol-withdrawal Seizures Are Controlled by Tissue Plasminogen Activator Via Modulation of NR2B-containing NMDA Receptors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Jan 5

PMID 15630096

Citations 66

Authors

Robert Pawlak

Jerry P Melchor

Tomasz Matys

Anna E Skrzypiec

Sidney Strickland

Affiliations

Soon will be listed here.

Abstract

Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1/2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.

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