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MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function

Arek Szklarczyk^*, Osefame Ewaleifoh^*, Jean-Claude Beique^,, Yue Wang, David Knorr^*, Norman Haughey^*, Tanya Malpica^*, Mark P. Mattson^,, Richard Huganir^, and Katherine Conant^*,1

^* Department of Neurology and

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;

Howard Hughes Medical Institute, Chevy Chase, Maryland, USA; and

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA

¹Correspondence: Johns Hopkins University, Department of Neurology, Pathology Bldg. Rm. 625, 600 N. Wolfe St., Baltimore, MD 21287, USA. E-mail: kconant{at}mail.jhmi.edu

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that play a role in the inflammatory response. These enzymes have been well studied in the context of cancer biology and inflammation. Recent studies, however, suggest that these enzymes also play roles in brain development and neurodegenerative disease. Select MMPs can target proteins critical to synaptic structure and neuronal survival, including integrins and cadherins. Here, we show that one member of the MMP family, MMP-7, which may be released from cells, including microglia, can target a protein critical to synaptic function. Through analysis of extracts from murine cortical slice preparations, we show that MMP-7 cleaves the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor to generate an N-terminal fragment of 65 kDa. Moreover, studies with recombinant protein show that MMP-7-mediated cleavage of NR1 occurs at amino acid 517, which is extracellular and just distal to the first transmembrane domain. Data suggest that NR2A, which shares sequence homology with NR1, is also cleaved following treatment of slices with MMP-7, while select AMPA receptor subunits are not. Consistent with a potential effect of MMP-7 on ligand binding, additional experiments demonstrate that NMDA-mediated calcium flux is significantly diminished by MMP-7 pretreatment of cultures. In addition, the AMPA/NMDA ratio is increased by MMP-7 pretreatment. These data suggest that synaptic function may be altered in neurological conditions associated with increased levels of MMP-7.—Szklarczyk, A., Ewaleifoh, O., Beique, J.-C., Wang, Y., Knorr, D., Haughey, N., Malpica, T., Mattson, M. P., Huganir, R., Conant, K. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function.

Key Words: matrilysin • glutamate • synapse • proteolysis

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