Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS).
• Tissue-type plasminogen activator (tPA) modulates glutamatergic neurotransmission, particularly NMDAR-mediated calcium signaling.
• Previous hypotheses suggested tPA directly cleaves the NR1 subunit of NMDAR to potentiate signaling.

Purpose of the Study:

• To investigate the mechanism by which tPA enhances NMDA receptor (NMDAR) signaling.
• To determine if tPA directly cleaves the NR1 subunit of NMDAR.
• To elucidate the role of plasminogen and identify potential mediators of tPA's effect on NMDAR function.

Main Methods:

• Assessed the requirement for tPA proteolytic activity in potentiating NMDAR signaling.
• Investigated the cleavage of the NR1 subunit and plasminogen by tPA.
• Utilized biochemical assays to identify the interaction between tPA, NMDAR, and other cellular components, including members of the low-density lipoprotein receptor (LDLR) family.

Main Results:

• The potentiation of NMDAR signaling by tPA requires its proteolytic activity but does not involve direct cleavage of the NR1 subunit or plasminogen.
• tPA enhances NMDAR function indirectly through interaction with a member of the LDLR family.
• Plasmin, in contrast to tPA, directly proteolyzes cell-surface NMDARs, indicating distinct mechanisms of action.

Conclusions:

• tPA indirectly modulates NMDA-induced events via engagement with an LDLR family member, not by direct cleavage of the NR1 subunit.
• Plasmin directly cleaves NMDARs, representing a distinct pathway for NMDAR modulation compared to tPA.
• This study reveals a novel functional relationship involving tPA, NMDAR, an LDLR, and a suspected serpin substrate.