Is tissue-type plasminogen activator a neuromodulator?

In the last few years, it has been evidenced that serine proteases play key roles in the mammalian brain, both in physiological and pathological conditions. It has been well established that among these serine proteases, the tissue-type plasminogen activator (t-PA) is critically involved in development, plasticity, and pathology of the nervous system. However, its mechanism of action remains to be further investigated. By using pharmacological and immunological approaches, we have evidenced in the present work that t-PA should be considered as a neuromodulator. Indeed, we have observed that: (i) neuronal depolarization induces a release of t-PA; (ii) this release of t-PA is sensitive to exocytosis inhibition and calcium chelation; (iii) released t-PA modulates NMDA receptor signaling and (iv) astrocytes are able to recapture extracellular t-PA through a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent mechanism.