Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extracellular matrix at the neuromuscular junction plays many roles. The matrix plays a structural role in that it maintains the spatial relationship between the muscle cell, Schwann cell, and presynaptic motor neuron. The matrix also plays a role in cell-to-cell signaling. The most studied member of this group is the heparan sulfate proteoglycan, agrin. Agrin is an integral member of the synaptic matrix, and it plays the pivotal role of instructing the muscle cell to aggregate acetylcholine receptors (AChRs) to the synapse. Agrin is released by the motor neuron, where it binds stably to the extracellular matrix. Agrin interacts with the muscle-specific tyrosine kinase (MuSK). Mice that lack agrin, or MuSK, fail to form neuromuscular junctions. Thus, the extracellular matrix is critical to both the structure and function of the neuromuscular junction. Remodeling of the extracellular matrix at the neuromuscular junction is needed to maintain stability, to allow growth, or to destabilize and remove synapses. Matrix metalloproteinases are key regulators of the extracellular matrix. In particular, matrix metalloproteinase 3 (MMP3) has been implicated in regulation of synaptic structure. MMP3 cleaves agrin. Antibodies to MMP3 recognize molecules concentrated at the synapses of frog neuromuscular junctions. Neuromuscular junctions in MMP3 null mutant mice have increased junctional folds, and AChR aggregates. Changes in synaptic activity will alter the activity of MMP3 at the synapse. Thus, the extracellular matrix is critical to the formation of the synapse, and synaptic activity controls the structure and function of the molecules in the extracellular matrix.
 ...
PMID:Cell-to-cell signaling at the neuromuscular junction: the dynamic role of the extracellular matrix. 1856 49

Interaction between extracellular matrix proteins and regulatory proteinases can mediate synaptic integrity. Previously, we documented that matrix metalloproteinase 3 (MMP-3) expression and activity increase following traumatic brain injury (TBI). We now report protein and mRNA analysis of agrin, a MMP-3 substrate, over the time course of trauma-induced synaptogenesis. Agrin expression during the successful synaptic reorganization of unilateral entorhinal cortical lesion (UEC) was compared with expression when normal synaptogenesis fails (combined fluid percussion TBI and bilateral entorhinal lesion [BEC]). We observed that agrin protein was increased in both models at 2 and 7 days postinjury, and immuohistochemical (IHC) co-localization suggested reactive astrocytes contribute to that increase. Agrin formed defined boundaries for sprouting axons along deafferented dendrites in the UEC, but failed to do so after combined insult. Similarly, Western blot analysis revealed greater increase in UEC agrin protein relative to the combined TBI+BEC model. Both models showed increased agrin transcription at 7 days postinjury and mRNA normalization by 15 days. Attenuation of synaptic pathology with the NMDA antagonist MK-801 reduced 7-day UEC agrin transcript to a level not different from unlesioned controls. By contrast, MK-801 in the combined insult failed to significantly change 7-day agrin transcript, mRNA levels remaining elevated over uninjured sham cases. Together, these results suggest that agrin plays an important role in the sprouting phase of reactive synaptogenesis, and that both its expression and distribution are correlated with extent of successful recovery after TBI. Further, when pathogenic conditions which induce synaptic plasticity are reduced, increase in agrin mRNA is attenuated.
 ...
PMID:Agrin expression during synaptogenesis induced by traumatic brain injury. 1862 55