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

Samson, Andre L., Nevin, Simon T., Croucher, David, Niego, Be'eri, Daniel, Philip B., Weiss, Thomas W., Moreno, Eliza, Monard, Denis, Lawrence, Daniel A. and Medcalf, Robert L. (2008) Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. Journal Of Neurochemistry, 107 4: 1091-1101. doi:10.1111/j.1471-4159.2008.05687.x


Author Samson, Andre L.
Nevin, Simon T.
Croucher, David
Niego, Be'eri
Daniel, Philip B.
Weiss, Thomas W.
Moreno, Eliza
Monard, Denis
Lawrence, Daniel A.
Medcalf, Robert L.
Title Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function
Journal name Journal Of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
1471-4159
Publication date 2008-09-15
Year available 2008
Sub-type Article (original research)
DOI 10.1111/j.1471-4159.2008.05687.x
Open Access Status Not yet assessed
Volume 107
Issue 4
Start page 1091
End page 1101
Total pages 11
Editor Turner, Anthony J.
Place of publication United Kingdom
Publisher Wiley- Blackwell Publishing Ltd
Language eng
Subject C1
1109 Neurosciences
920111 Nervous System and Disorders
Abstract 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.
Keyword Low-density lipoprotein receptor family
NMDA receptor
Plasmin
Serine protease inhibitor
Tissue-type plasminogen activator
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Queensland Brain Institute Publications
 
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Created: Fri, 20 Mar 2009, 21:06:43 EST by Debra McMurtrie on behalf of Queensland Brain Institute