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

Andre L Samson,Denis Monard,Robert L Medcalf,David Croucher,Daniel A Lawrence,Eliza Moreno,Be’Eri Niego,Simon T Nevin,Thomas W Weiss,Philip B Daniel

doi:10.1111/j.1471-4159.2008.05687.x

Andre L Samson, Denis Monard + Show 8 more

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https://doi.org/10.1111/j.1471-4159.2008.05687.x

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Journal: Journal of Neurochemistry	Publication Date: Oct 21, 2008
Citations: 114	License type: cc-by

Affiliation: Monash University

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Glutamate is the main excitatory neurotransmitter of the CNS. Tissue-type plasminogen activator (tPA) is recognized as a modulator of glutamatergic neurotransmission. This attribute is exemplified by its ability to potentiate calcium signaling following activation of the glutamate-binding NMDA receptor (NMDAR). It has been hypothesized that tPA can directly cleave the NR1 subunit of the NMDAR and thereby potentiate NMDA-induced calcium influx. In contrast, here we show that this increase in NMDAR signaling requires tPA to be proteolytically active, but does not involve cleavage of the NR1 subunit or plasminogen. Rather, we demonstrate that enhancement of NMDAR function by tPA is mediated by a member of the low-density lipoprotein receptor (LDLR) family. Hence, this study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. Interestingly, whilst tPA alone failed to cleave NR1, cell-surface NMDARs did serve as an efficient and discrete proteolytic target for plasmin. Hence, plasmin and tPA can affect the NMDAR via distinct avenues. Altogether, we find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement.

Highlights

This study proposes a novel functional relationship between type plasminogen activator (tPA), the NMDA receptor (NMDAR), a low-density lipoprotein receptor (LDLR) and an unknown substrate which we suspect to be a serpin
The mechanism by which tPA increases NMDAR signaling appears to be more complicated that first hypothesized. In line with this notion, we show that the ability of tPA to augment NMDA-induced D[Ca2+]i requires a member of the low-density lipoprotein receptor (LDLR) family
In support of a multifactorial mechanism, we find that tPA does not alter NMDARmediated currents in an expressed heterologous Xenopus oocyte system, suggesting that additional cellular factors present in neuronal cultures are necessary for tPA to modulate NMDAR function

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This study proposes a novel functional relationship between tPA, the NMDAR, a LDLR and an unknown substrate which we suspect to be a serpin. We find that plasmin directly proteolyses the NMDAR whilst tPA functions as an indirect modulator of NMDA-induced events via LDLR engagement. The serine protease, tissue-type plasminogen activator (tPA), is known for its ability to cleave the pro-enzyme plasminogen into the potent protease plasmin, which can in turn lyse blood clots via the digestion of fibrin. In addition to this vascular role, tPA is recognized to perform important roles within the brain (Melchor and Strickland 2005; Samson and Medcalf 2006). The mechanism by which tPA increases NMDAR signaling appears to be more complicated that first hypothesized In line with this notion, we show that the ability of tPA to augment NMDA-induced D[Ca2+]i requires a member of the low-density lipoprotein receptor (LDLR) family. TPA has a dual influence on the NMDAR: one being the indirect potentiation of calcium flux via LDLR engagement, and the other being the plasmin-dependent proteolysis of NR1

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