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J Neurochem
2008 Nov 01;1074:1091-101. doi: 10.1111/j.1471-4159.2008.05687.x.
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Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function.
Samson AL
,
Nevin ST
,
Croucher D
,
Niego B
,
Daniel PB
,
Weiss TW
,
Moreno E
,
Monard D
,
Lawrence DA
,
Medcalf RL
.
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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.
Backes,
Synthesis of positional-scanning libraries of fluorogenic peptide substrates to define the extended substrate specificity of plasmin and thrombin.
2000, Pubmed
Backes,
Synthesis of positional-scanning libraries of fluorogenic peptide substrates to define the extended substrate specificity of plasmin and thrombin.
2000,
Pubmed
Benchenane,
Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
2007,
Pubmed
Boucher,
LRP: role in vascular wall integrity and protection from atherosclerosis.
2003,
Pubmed
Clark,
The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1.
2006,
Pubmed
,
Xenbase
Fernández-Monreal,
Is tissue-type plasminogen activator a neuromodulator?
2004,
Pubmed
Fernández-Monreal,
Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-D-aspartate receptor signaling.
2004,
Pubmed
Fredriksson,
Tissue plasminogen activator is a potent activator of PDGF-CC.
2004,
Pubmed
Gingrich,
Potentiation of NMDA receptor function by the serine protease thrombin.
2000,
Pubmed
Gosalia,
Profiling serine protease substrate specificity with solution phase fluorogenic peptide microarrays.
2005,
Pubmed
Granelli-Piperno,
A study of proteases and protease-inhibitor complexes in biological fluids.
1978,
Pubmed
Harris,
Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries.
2000,
Pubmed
Hastings,
Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival.
1997,
Pubmed
Herz,
LRP: a multifunctional scavenger and signaling receptor.
2001,
Pubmed
Horn,
Molecular analysis of ligand binding to the second cluster of complement-type repeats of the low density lipoprotein receptor-related protein. Evidence for an allosteric component in receptor-associated protein-mediated inhibition of ligand binding.
1997,
Pubmed
Hu,
Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression.
2006,
Pubmed
Huggins,
The function of the amino terminal domain in NMDA receptor modulation.
2005,
Pubmed
Kloda,
Voltage-dependent inhibition of recombinant NMDA receptor-mediated currents by 5-hydroxytryptamine.
2005,
Pubmed
,
Xenbase
Kumada,
Tissue type plasminogen activator facilitates NMDA-receptor-mediated retinal apoptosis through an independent fibrinolytic cascade.
2005,
Pubmed
Kvajo,
Regulation of brain proteolytic activity is necessary for the in vivo function of NMDA receptors.
2004,
Pubmed
Lawrence,
Serpin-protease complexes are trapped as stable acyl-enzyme intermediates.
1995,
Pubmed
Liot,
2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo.
2004,
Pubmed
Liu,
Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C.
2004,
Pubmed
Lochner,
Activity-dependent release of tissue plasminogen activator from the dendritic spines of hippocampal neurons revealed by live-cell imaging.
2006,
Pubmed
Makarova,
The low density lipoprotein receptor-related protein modulates protease activity in the brain by mediating the cellular internalization of both neuroserpin and neuroserpin-tissue-type plasminogen activator complexes.
2003,
Pubmed
Martin,
The functional role of the second NPXY motif of the LRP1 beta-chain in tissue-type plasminogen activator-mediated activation of N-methyl-D-aspartate receptors.
2008,
Pubmed
Matys,
Tissue plasminogen activator and NMDA receptor cleavage.
2003,
Pubmed
May,
Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice.
2004,
Pubmed
Medina,
Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation.
2005,
Pubmed
Meier,
Induction of glia-derived nexin after lesion of a peripheral nerve.
1989,
Pubmed
Melchor,
Tissue plasminogen activator in central nervous system physiology and pathology.
2005,
Pubmed
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group,
Tissue plasminogen activator for acute ischemic stroke.
1995,
Pubmed
Nicole,
The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.
2001,
Pubmed
Norris,
Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system.
2007,
Pubmed
Orth,
Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator.
1994,
Pubmed
Park,
Key role of tissue plasminogen activator in neurovascular coupling.
2008,
Pubmed
Pawlak,
Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors.
2005,
Pubmed
Pawlak,
Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus.
2005,
Pubmed
Pawlak,
Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice.
2002,
Pubmed
Polavarapu,
Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit.
2007,
Pubmed
Qiu,
ApoE isoforms affect neuronal N-methyl-D-aspartate calcium responses and toxicity via receptor-mediated processes.
2003,
Pubmed
Qiu,
alpha 2-Macroglobulin exposure reduces calcium responses to N-methyl-D-aspartate via low density lipoprotein receptor-related protein in cultured hippocampal neurons.
2002,
Pubmed
Reddrop,
Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury.
2005,
Pubmed
Rossignol,
Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells.
2004,
Pubmed
Samson,
Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity.
2006,
Pubmed
Schaefer,
The plasminogen activator system modulates sympathetic nerve function.
2006,
Pubmed
Schaefer,
Modulation of sympathetic activity by tissue plasminogen activator is independent of plasminogen and urokinase.
2007,
Pubmed
Su,
Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.
2008,
Pubmed
Verheijen,
A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma.
1982,
Pubmed
Vincent,
Role of astrocyte-derived tissue-type plasminogen activator in the regulation of endotoxin-stimulated nitric oxide production by microglial cells.
1998,
Pubmed
Wang,
Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice.
1998,
Pubmed
Weiss,
Oncostatin M is a neuroprotective cytokine that inhibits excitotoxic injury in vitro and in vivo.
2006,
Pubmed
Wolosker,
Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter.
2002,
Pubmed
Xia,
An ER retention signal explains differences in surface expression of NMDA and AMPA receptor subunits.
2001,
Pubmed
Xue,
Selective inhibitors of the serine protease plasmin: probing the S3 and S3' subsites using a combinatorial library.
2005,
Pubmed
Yang,
Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine.
2003,
Pubmed
Yepes,
Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein.
2003,
Pubmed
Yepes,
Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent.
2002,
Pubmed
Zhuo,
Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation.
2000,
Pubmed
