Endothelial protein C receptor is expressed in rat cortical and hippocampal neurons and is necessary for protective effect of activated protein C at glutamate excitotoxicity

Горбачева, Л. Р.; Davidova, Olga; Sokolova, Elena; Ishiwata, Shin’ichi; Pinelis, V. G.; Strukova, S. M.; Reiser, Georg

doi:10.1111/j.1471-4159.2009.06380.x

Cited by 32 publications

(23 citation statements)

References 42 publications

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“…The authors proposed a model in which PAR-PLC␤-DGL␣ pathways mediate thrombin-induced 2-AG production. It has been reported that rat cultured hippocampal neurons exhibit PAR1-immnoreactivtiy and expression of mRNA (Gorbacheva et al, 2009). Furthermore, the study using Ca 2ϩ -imaging has demonstrated the presence of functional PAR1 in cultured hippocampal neurons (Bushell et al, 2006).…”

Section: Discussionmentioning

confidence: 93%

Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol

Hashimotodani¹,

Ohno‐Shosaku²,

Yamazaki³

et al. 2011

J. Neurosci.

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Protease-activated receptor 1 (PAR1) is a member of the G-protein coupled receptors that are proteolytically activated by serine proteases. Recent studies suggest a definite contribution of PAR1 to brain functions, including learning and memory. However, cellular mechanisms by which PAR1 activation influences neuronal activity are not well understood. Here we show that PAR1 activation drives retrograde endocannabinoid signaling and thereby regulates synaptic transmission. In cultured hippocampal neurons from rat, PAR1 activation by thrombin or PAR1-specific peptide agonists transiently suppressed inhibitory transmission at cannabinoid-sensitive, but not cannabinoid-insensitive, synapses. The PAR1-induced suppression of synaptic transmission was accompanied by an increase in paired-pulse ratio, and was blocked by a cannabinoid CB 1 receptor antagonist. The PAR1-induced suppression was blocked by pharmacological inhibition of postsynaptic diacylglycerol lipase (DGL), a key enzyme for biosynthesis of the major endocannabinoid 2-arachidonoylglycerol (2-AG), and was absent in knock-out mice lacking the ␣ isoform of DGL. The PAR1-induced IPSC suppression remained intact under the blockade of metabotropic glutamate receptors and was largely resistant to the treatment that blocked Ca 2ϩ elevation in glial cells following PAR1 activation, which excludes the major contribution of glial PAR1 in IPSC suppression. We conclude that activation of neuronal PAR1 triggers retrograde signaling mediated by 2-AG, which activates presynaptic CB 1 receptors and suppresses transmitter release at hippocampal inhibitory synapses.

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Section: Discussionmentioning

confidence: 93%

Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol

Hashimotodani¹,

Ohno‐Shosaku²,

Yamazaki³

et al. 2011

J. Neurosci.

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“…Although originally identified as an endothelial cell receptor, EPCR has since been detected in a number of cell types, including vascular smooth muscle cells [11], eosinophils [12], neutrophils [13], monocytes [14], keratinocytes [15], hippocampal neurons [16], cardiomyocytes [17], and placental trophoblasts [18]. EPCR was recently shown to be expressed on the surface of bone marrow [19] and fetal liver embryonic hematopoietic stem cells (HSCs) [20].…”

Section: Introductionmentioning

confidence: 99%

The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling

Gleeson

O’Donnell

Preston

2011

Cell. Mol. Life Sci.

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Increasing evidence links blood coagulation proteins with the regulation of acute and chronic inflammatory disease. Of particular interest are vitamin K-dependent proteases, which are generated as a hemostatic response to vascular injury, but can also initiate signal transduction via interactions with vascular receptors. The endothelial cell protein C receptor (EPCR) is a multi-ligand vitamin K-dependent protein receptor for zymogen and activated forms of plasma protein C and factor VII. Although the physiological role of the EPCR-FVII(a) interaction is not well-understood, protein C binding to EPCR facilitates rapid generation of APC in response to excessive thrombin generation, and is a central requirement for the multiple signal-transduction cascades initiated by APC on both vascular endothelial and innate immune cells. Exciting recent studies have highlighted the emerging role of EPCR in modulating the cytoprotective properties of APC in a number of diverse inflammatory disorders. In this review, we describe the structure-function relationships, signal transduction pathways, and cellular interactions that enable EPCR to modulate the anticoagulant and anti-inflammatory properties of its vitamin K-dependent protein ligands, and examine the relevance of EPCR to both thrombotic and inflammation-associated disease.

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“…Presumably, these processes in the infarction perifocal zone are stimulated by APC, characterized by anticoagulant, anti-infl ammatory, and cytoprotective effects [6,11]. The neuroprotective effect of recombinant APC without anticoagulant activity has been demonstrated [7].…”

Section: Resultsmentioning

confidence: 99%

“…One of the possible approaches is the use of activated protein C (APC), hemostasis proteinase with anticoagulant, anti-infl ammatory, and neuroprotective activities [6,7,11,15].…”

mentioning

confidence: 99%

Effects of Activated Protein C on the Size of Modeled Ischemic Focus and Morphometric Parameters of Neurons and Neuroglia in Its Perifocal Zone

et al. 2014

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The effects of activated protein C (APC) on the quantitative parameters of neurons and neuroglia in the perifocal zone of infarction induced in the left hemispheric cortex were studied in two groups of rats. Group 1 animals served as control (control infarction). Group 2 rats were injected with APC (50 μg/kg) in the right lateral cerebral ventricle 3 h after infarction was induced, and after 72 h the infarction size was evaluated and the neurons and neuroglia in the perifocal zone were counted. APC reduced the infarction size 2.5 times in comparison with the control and reduced by 16% the neuronal death in the perifocal zone layer V, causing no appreciable changes in layer III, and did not change the size of neuronal bodies but increased (by 11%) the size of neuronal nuclei in layer III. The protein maintained the sharply increased count of gliocytes in the perifocal zone of infarction and promoted their growth. Hence, APC protected the neurons from death in the ischemic focus by increasing the gliocyte count and stimulating the compensatory reparative processes.

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Endothelial protein C receptor is expressed in rat cortical and hippocampal neurons and is necessary for protective effect of activated protein C at glutamate excitotoxicity

Cited by 32 publications

References 42 publications

Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol

Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol

The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling

Effects of Activated Protein C on the Size of Modeled Ischemic Focus and Morphometric Parameters of Neurons and Neuroglia in Its Perifocal Zone

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