Beta-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity.
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.
Michaluk
Piotr
P
Department of Molecular and Cellular Neurobiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland.
Kolodziej
Lukasz
L
Mioduszewska
Barbara
B
Wilczynski
Grzegorz M
GM
Dzwonek
Joanna
J
Jaworski
Jacek
J
Gorecki
Dariusz C
DC
Ottersen
Ole Petter
OP
Kaczmarek
Leszek
L
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D049030:Dystroglycans / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000494:pharmacology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013569:Synapses / Q000201:enzymology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D018756:GABA Antagonists; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D049030:Dystroglycans; D018698:Glutamic Acid; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D001640:Bicuculline