Plasminogen activators and inhibitors in the neuromuscular system: III. The serpin protease nexin I is synthesized by muscle and localized at neuromuscular synapses

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Abstract
Recent studies suggest that the nature of events leading to the formation, maintenance, and elimination of synapses may be regulated by cascade‐type, locally expressed proteases and protease inhibitors acting on adhesive extracellular matrix components. We have identified a molecule in conditioned medium of murine skeletal muscle cells that in molecular weight, target protease inhibition, heparin‐binding and cross‐reactivity with authenic antisera is similar to the human serine proteinase inhibitor, protease nexin I. Protease nexin I is a 43–50 kDa glycoprotein of the serpin superfamily (arg‐serpin class). Purified anti‐protease nexin I antibody (anti‐47 kDa) stains adult mouse skeletal muscle in discrete foci that precisely superimpose on synaptic neuromuscular junctions. Protease nexin I appears in patches on surfaces of cultured mouse skeletal myotubes, but not on myoblasts. These patches co‐localize with acetylcholine receptor clusters and acetylcholinesterase staining during cellular maturation in culture. Evidence that protease nexin I is a synaptic, extracellular antigen is particularly intriguing since it has been shown to be identical, in structure and activity, with a factor released by glial cells, called glia‐derived nexin that stimulates mouse neuroblastoma cell neurite outgrowth and inhibits granule cell migration Protease nexin I inhibits both tumor cell and myoblast plasminogen activator‐mediated destruction of extracellular matrix. Thus, such observations as presented in this report provide further evidence for involvement of cascade proteolytic systems, and their post‐translational regulation by specific serpins, in the remodeling that occurs in synapse formation and elimination.

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