Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function.
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.
Samson
Andre L
AL
Australian Centre for Blood Diseases, Monash University, AMREP, Melbourne, Victoria, Australia.
Nevin
Simon T
ST
Croucher
David
D
Niego
Be'eri
B
Daniel
Philip B
PB
Weiss
Thomas W
TW
Moreno
Eliza
E
Monard
Denis
D
Lawrence
Daniel A
DA
Medcalf
Robert L
RL
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D005341:Fibrinolysin / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D009865:Oocytes; D018408:Patch-Clamp Techniques; D058255:Protease Nexins; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014982:Xenopus laevis; D020668:rap GTP-Binding Proteins / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D020668:rap GTP-Binding Proteins; D002118:Calcium; D005998:Glycine
Nat Med. 2008 Jul;14(7):731-7
18568034
FASEB J. 2006 Nov;20(13):2369-71
17023520
J Biol Chem. 2008 May 2;283(18):12004-13
18321860
Proteomics. 2005 Apr;5(5):1292-8
15742319
J Biol Chem. 2002 Apr 26;277(17):14458-66
11839752
Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1504-7
15790922
N Engl J Med. 1995 Dec 14;333(24):1581-7
7477192
J Neurosci. 2004 Oct 27;24(43):9734-43
15509762
J Cell Sci. 2007 Feb 15;120(Pt 4):578-85
17244650
Neuropharmacology. 2001 Nov;41(6):714-23
11640925
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13473-8
17673549
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18201-6
16330749
Science. 2003 Apr 11;300(5617):329-32
12690199
Nat Med. 1998 Feb;4(2):228-31
9461198
Mol Cell Neurosci. 2004 Apr;25(4):594-601
15080889
J Clin Invest. 2002 Jun;109(12):1571-8
12070304
Br J Pharmacol. 2005 Feb;144(3):323-30
15655527
Nat Med. 2003 Apr;9(4):371-2; author reply 372-3
12669038
J Biol Chem. 1997 May 23;272(21):13608-13
9153209
Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):443-8
15630096
J Biol Chem. 1994 Aug 19;269(33):21117-22
8063731
J Pharmacol Exp Ther. 2007 Jul;322(1):265-73
17429057
J Neurosci. 2000 Jun 15;20(12):4582-95
10844028
Neuron. 2006 Jun 1;50(5):673-8
16731507
J Exp Med. 1978 Jul 1;148(1):223-34
78958
Neurochem Int. 2002 Nov;41(5):327-32
12176074
J Clin Invest. 2003 Nov;112(10):1533-40
14617754
Blood. 2007 Apr 15;109(8):3270-8
17170123
J Biol Chem. 2003 Dec 12;278(50):50250-8
14522960
Nat Med. 2004 Dec;10(12):1379-83
15516929
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15194-9
14638938
Neuroscience. 2003;122(2):291-303
14614897
Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1073-8
18195371
J Neurobiol. 2006 May;66(6):564-77
16555239
J Biol Chem. 1995 Oct 27;270(43):25309-12
7592687
J Biol Chem. 2006 Aug 11;281(32):23254-63
16754662
J Clin Invest. 2001 Sep;108(6):779-84
11560943
Mol Cell Biol. 2004 Oct;24(20):8872-83
15456862
Glia. 1998 Feb;22(2):130-7
9537833
J Biol Chem. 2004 Mar 12;279(11):10346-56
14699093
J Biol Chem. 2004 Dec 3;279(49):50850-6
15448144
J Biol Chem. 2006 Jan 27;281(4):2120-7
16303771
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7754-9
10869434
J Exp Med. 2006 Sep 4;203(9):2191-200
16940168
Nat Med. 2001 Jan;7(1):59-64
11135617
J Neurosci. 2000 Jan 15;20(2):542-9
10632583
J Mol Graph Model. 2005 Jan;23(4):381-8
15670959
Neuroscience. 2002;113(4):995-1001
12182903
Nat Biotechnol. 2000 Feb;18(2):187-93
10657126
Stroke. 2005 Jun;36(6):1241-6
15879331
J Biol Chem. 1997 Dec 26;272(52):33062-7
9407089
EMBO J. 2004 Oct 1;23(19):3793-802
15372073
EMBO J. 2005 May 4;24(9):1706-16
15861134
Thromb Haemost. 2005 Apr;93(4):655-60
15841309
Thromb Haemost. 1982 Dec 27;48(3):266-9
6891841
J Cereb Blood Flow Metab. 2004 Oct;24(10):1153-9
15529015
J Med Chem. 2005 Nov 3;48(22):6908-17
16250649
Nature. 1989 Nov 30;342(6249):548-50
2685611