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J. Biol. Chem., Vol. 282, Issue 22, 16036-16041, June 1, 2007

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-Dystroglycan as a Target for MMP-9, in Response to Enhanced Neuronal Activity^*

Piotr Michaluk, Lukasz Kolodziej, Barbara Mioduszewska, Grzegorz M. Wilczynski^¶, Joanna Dzwonek, Jacek Jaworski^||, Dariusz C. Gorecki^**, Ole Petter Ottersen, and Leszek Kaczmarek¹

From the Department of Molecular and Cellular Neurobiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland, the ^¶Department of Neurophysiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland, the Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands, the ^||Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland, the ^**Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Science, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, United Kingdom, and the Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, Domus Medica (Sognsvannsveien 9), University of Oslo, N-0317 Oslo, Norway

Matrix metalloproteinase-9 has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. However, no synaptic targets for its enzymatic activity had been identified before. In this report, we show that -dystroglycan comprises such a neuronal activity-driven target for matrix metalloproteinase-9. This notion is based on the following observations. (i) Recombinant, autoactivating matrix metalloproteinase-9 produces limited proteolytic cleavage of -dystroglycan. (ii) In neuronal cultures, -dystroglycan proteolysis occurs in response to stimulation with either glutamate or bicuculline and is blocked by tissue inhibitor of metalloproteinases-1, a metalloproteinase inhibitor. (iii) -Dystroglycan degradation is also observed in the hippocampus in vivo in response to seizures but not in the matrix metalloproteinase-9 knock-out mice. (iv) -Dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, -dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the -dystroglycan as a first matrix metalloproteinase-9 substrate digested in response to enhanced synaptic activity. This demonstration may help to understand the possible role of both proteins in neuronal functions, especially in synaptic plasticity, learning, and memory.

Received for publication, January 23, 2007 , and in revised form, April 6, 2007.

^* This work was supported by The Polish Ministry of Science and Higher Education Research Grant 2 P04A 009 30, a grant from The Welcome Trust, and Grant GRIPANNT from the Sixth Framework Program of European Union. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 48-22-659-3001; Fax: 48-22-822-5342; E-mail: l.kaczmarek{at}nencki.gov.pl.

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