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Beta-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity
Piotr Michaluk1, Lukasz Kolodziej, Barbara Mioduszewska
1Department of Molecular and Cellular Neurobiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland.
Abstract:
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 beta-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 beta-dystroglycan. (ii) In neuronal cultures, beta-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) Beta-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) Beta-dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, beta-dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the beta-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.
Insights
Matrix metalloproteinase-9 (MMP-9) cleaves beta-dystroglycan, a newly identified synaptic target. This MMP-9 activity in synaptic plasticity, learning, and memory is crucial.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Matrix metalloproteinase-9 (MMP-9) is implicated in regulating extracellular proteolysis in synaptic plasticity.
- Specific neuronal targets for MMP-9 enzymatic activity remained unidentified prior to this study.
Purpose of the Study:
- To identify neuronal activity-driven substrates of matrix metalloproteinase-9 (MMP-9).
- To investigate the role of beta-dystroglycan as a target of MMP-9 in synaptic function.
Main Methods:
- In vitro assays with recombinant MMP-9 and beta-dystroglycan.
- Neuronal cultures stimulated with glutamate or bicuculline, treated with tissue inhibitor of metalloproteinases-1.
- In vivo studies in mouse hippocampus during seizures, comparing wild-type and MMP-9 knockout mice.
- Assessment of MMP-9 activity and colocalization with beta-dystroglycan in postsynaptic elements.
Main Results:
- Recombinant MMP-9 demonstrated limited proteolytic cleavage of beta-dystroglycan.
- Beta-dystroglycan proteolysis was observed in stimulated neuronal cultures and during in vivo seizures, and was inhibited by a metalloproteinase inhibitor.
- Proteolysis was absent in MMP-9 knockout mice and correlated with increased MMP-9 activity.
- Beta-dystroglycan and MMP-9 were found to colocalize in hippocampal postsynaptic elements.
Conclusions:
- Beta-dystroglycan is identified as the first neuronal activity-driven substrate of matrix metalloproteinase-9 (MMP-9).
- This finding provides insight into the function of MMP-9 and beta-dystroglycan in synaptic plasticity, learning, and memory.