MEMBRANE DEPOLARIZATION INDUCES CALCIUM-DEPENDENT SECRETION OF TISSUE-PLASMINOGEN ACTIVATOR

Tissue plasminogen activator (tPA), a serine protease that converts in active plasminogen to active plasmin, is produced in the rat and mouse hippocampus and participates in neuronal plasticity. To help define t he role of tPA in the nervous system, we have analyzed the regulation of its expression in the neuronal cell line PC12. In control cultures, tPA activity is exclusively cell-associated, and no activity is measu rable in the culture medium. When the cells are treated with depolariz ing agents, such as KCI, tPA activity becomes detectable in the medium . The increased secreted tPA activity is not accompanied by an increas e in tPA mRNA levels, and it is not blocked by protein synthesis inhib itors. in contrast, tPA release is abolished by Ca2+ channel blockers, suggesting that chemically induced membrane depolarization stimulates the secretion of preformed enzyme. Moreover, KCl has a similar effect in vivo when administered to the murine brain via an osmotic pump: tP A activity increases along the CA2-CA3 regions and dentate gyrus of th e hippocampal formation. These results demonstrate a neuronal activity -dependent secretory mechanism that can rapidly increase the amount of tPA in neuronal tissue.