Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 4536K) PDF+supp data (6393K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, Z.-L. Articles by Strickland, S. Search for Related Content PubMed PubMed Citation Articles by Chen, Z.-L. Articles by Strickland, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH Related Collections Related In this Issue article Social Bookmarking                            What's this?

Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor

¹ Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065
² Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, England, UK

Correspondence to Sidney Strickland: strickland{at}rockefeller.edu

Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin 1 (lam1) expression in the hippocampus. Lam1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lam1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lam1 KO mice. KA1 levels in tissue plasminogen activator (tPA)–KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lam1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

Abbreviations used in this paper: ANOVA, analysis of variance; CaMKII, calcium/calmodulin-dependent protein kinase II ; DG, dentate gyrus; FJB, Fluoro Jade B; KA, kainate; KO, knockout; lam1, laminin 1; MKK4, MAPK kinase 4; tPA, tissue plasminogen activator.

© 2008 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related In this Issue article

Matrix fragments trigger fatal excitement

Mitch Leslie
J. Cell Biol. 2008 183: 1179. [Full Text] [PDF]

This article has been cited by other articles:

• Leslie, M. (2008). Matrix fragments trigger fatal excitement. JCB 183: 1179-1179 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents