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Journal of Neuroscience, Vol 16, 2220-2225, Copyright © 1996 by Society for Neuroscience
Membrane depolarization induces calcium-dependent secretion of tissue plasminogen activator
A Gualandris, TE Jones, S Strickland and SE Tsirka
Department of Pharmacology, University Medical Center at Stony Brook, New York 11794-8651, USA.
Tissue plasminogen activator (tPA), a serine protease that converts
inactive plasminogen to active plasmin, is produced in the rat and mouse
hippocampus and participates in neuronal plasticity. To help define the
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 measurable in
the culture medium. When the cells are treated with depolarizing agents,
such as KCI, tPA activity becomes detectable in the medium. The increased
secreted tPA activity is not accompanied by an increase in tPA mRNA levels,
and it is not blocked by protein synthesis inhibitors. In contrast, tPA
release is abolished by Ca2+ channel blockers, suggesting that chemically
induced membrane depolarization stimulates the secretion of preformed
enzyme. Moreover, KCI has a similar effect in vivo when administered to the
murine brain via an osmotic pump: tPA activity increases along the CA2-CA3
regions and dentate gyrus of the hippocampal formation. These results
demonstrate a neuronal activity-dependent secretory mechanism that can
rapidly increase the amount of tPA in neuronal tissue.
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January 17, 1997;
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