To the editor—It is established that the serine protease tissue plasminogen activator (TPA) and its conventional zymogen substrate plasminogen have an important role in certain central nervous system pathologies related to neuronal death (ref. 1 and references therein). Studies of rodents indicate that TPA and plasminogen synthesized locally2 or entering brain tissue through a compromised blood-brain barrier1 can be involved in this phenomenon. Whereas some of these central effects of TPA are associated with the conversion of plasminogen to plasmin, others are independent of plasminogen activation (reviewed in ref. 3). The identity of the substrate (s) for TPA that could mediate the action of this protease in the absence of plasminogen is still a matter of debate.

One possible substrate for TPA could be the N-methyl-D-aspartate (NMDA) receptor, as TPA can influence NMDA-mediated effects. Disruption of the gene encoding TPA, Plat, in mice interferes with the NMDA-dependent induction of long-term potentiation in the striatum4, suggesting that endogenous TPA can modulate NMDA receptor signaling. In the January 2001 issue of