Injury‐Related Factors and Conditions Down‐Regulate the Thrombin Receptor (PAR‐1) in a Human Neuronal Cell Line

Weinstein, Jonathan R.; Lau, Alice; Brass, Lawrence F.; Cunningham, Dennis D.

doi:10.1046/j.1471-4159.1998.71031034.x

Cited by 24 publications

(18 citation statements)

References 87 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous study, low concentrations of thrombin may also cause cell death after stroke. For example, a small dose of exogenous thrombin exacerbates ischemic brain injury 3, 23, 24 . It has been shown that systemic thrombin inhibition attenuated neurodegeneration and brain edema formation after transient cerebral ischemia 25, 26 .…”

Section: Discussionmentioning

confidence: 99%

Role of Protease-Activated Receptor-1 in Brain Injury After Experimental Global Cerebral Ischemia

Wang

Jin

Hua

et al. 2012

Stroke

View full text Add to dashboard Cite

Background Evidence suggests that the protease-activated receptor-1 (PAR-1), a thrombin receptor, mediates neuronal injury in experimental cerebral ischemia. The present study investigated whether PAR-1 plays a role in brain injury after global cerebral ischemia. Methods Adult male wild type (WT) or PAR-1 knockout mice underwent a 20-minute bilateral common carotid artery occlusion (BCCAO) or a sham operation. Behavior tests were performed before ischemia, and 1, 2 and 3 days after BCCAO. Mice were euthanized at different time points for thrombin activity, brain edema, Western blot analysis and brain histology. Results Thrombin activity and PAR-1 expression were increased in the brain after BCCAO. Compared with WT mice, PAR-1 knockout mice had less brain edema formation, neuronal death and behavior impairment after BCCAO. In addition, BCCAO-induced activation of mitogen-activated protein kinases was absent in PAR-1 knockout mice. Conclusion PAR-1 contributes to the brain injury induced by global cerebral ischemia, which may be related to activation of mitogen-activated protein kinases.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of Protease-Activated Receptor-1 in Brain Injury After Experimental Global Cerebral Ischemia

Wang

Jin

Hua

et al. 2012

Stroke

View full text Add to dashboard Cite

show abstract

“…Weinstein et al. examining Ad12 HER 10 cells, found that thrombin concentrations as low as 1.2 × 10 −3 U/mL caused cell death in hypoglycemic (0.1 m m glucose) but not in normoglycemic conditions (Weinstein et al . 1998).…”

Section: Thrombin‐induced Brain Injurymentioning

confidence: 99%

The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective?

Xi¹,

Reiser

Keep

2002

Journal of Neurochemistry

328

280

View full text Add to dashboard Cite

In the last two decades it has become apparent that thrombin has many extravascular effects that are mediated by a family of protease-activated receptors (PARs). PAR-1, -3 and -4 are activated via cleavage by thrombin. The importance of extravascular thrombin in modulating ischemic, hemorrhagic and traumatic injury in brain has recently become clear. Thus, in vitro, thrombin at low concentration protects neurons and astrocytes from cell death caused by a number of different insults. In vivo, pretreating the brain with a low dose of thrombin (thrombin preconditioning), attenuates the brain injury induced by a large dose of thrombin, an intracerebral hemorrhage or by focal cerebral ischemia. Thrombin may also be an important mediator of ischemic preconditioning. In contrast, high doses of thrombin kill neurons and astrocytes in vitro and cause disruption of the blood-brain barrier, brain edema and seizures in vivo. This review examines the role of thrombin in brain injury and the molecular mechanisms and signaling cascades involved.

show abstract

“…We transfected a plasmid expressing a bicistronic mRNA encoding dominant negative CKB and an enhanced green fluorescent protein reporter gene (EGFP) into human neuronal retinoblast cells (Ad12HER10) and observed the effect on PAR-1 signaling. The response to thrombin in these human neuronal cells has been extensively characterized and was especially suited for transfecting human CKB constructs (39,40). Most cells expressing EGFP vector alone displayed round refractile cell bodies (Fig.…”

Section: Dominant Negative Ckb Blocks Shape Changes In Retinoblastsmentioning

confidence: 99%

Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton

Mahajan

Pai²,

Lau³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Thrombin orchestrates cellular events after injury to the vascular system and extravasation of blood into surrounding tissues. The pathophysiological response to thrombin is mediated by proteaseactivated receptor-1 (PAR-1), a seven-transmembrane G proteincoupled receptor expressed in the nervous system that is identical to the thrombin receptor in platelets, fibroblasts, and endothelial cells. Once activated by thrombin, PAR-1 induces rapid and dramatic changes in cell morphology, notably the retraction of growth cones, axons, and dendrites in neurons and processes in astrocytes. The signal is conveyed by a series of localized ATP-dependent reactions directed to the actin cytoskeleton. How cells meet the dynamic and localized energy demands during signal transmission is unknown. Using the yeast two-hybrid system, we identified an interaction between PAR-1 cytoplasmic tail and the brain isoform of creatine kinase, a key ATP-generating enzyme that regulates ATP within subcellular compartments. The interaction was confirmed in vitro and in vivo. Reducing creatine kinase levels or its ATP-generating potential inhibited PAR-1-mediated cellular shape changes as well as a PAR-1 signaling pathway involving the activation of RhoA, a small G protein that relays signals to the cytoskeleton. Thrombin-stimulated intracellular calcium release was not affected. Our results suggest that creatine kinase is bound to PAR-1 where it may be poised to provide bursts of site-specific high-energy phosphate necessary for efficient receptor signal transduction during cytoskeletal reorganization. P rotease activated receptor-1 (PAR-1) mediates the cellular responses to thrombin during blood coagulation, cell proliferation, vascular permeability changes, tumor metastasis, and nervous system injury (1-3). PAR-1 is a seven-transmembrane G protein-coupled receptor with a novel activation mechanism. Proteolysis at a thrombin cleavage site in the extracellular amino terminus exposes a new amino terminus containing the peptide ligand SFLLRN, which binds intramolecularly to initiate intracellular signals (4). Although originally detected in platelets, endothelial cells, and fibroblasts, PAR-1 is also expressed in the nervous system in a developmentally regulated manner and by specific subpopulations of neurons and astrocytes that are especially vulnerable to neurodegeneration and ischemic injury (1,5,6).In most cells expressing PAR-1, activation of the receptor transmits signals to the actin cytoskeleton that profoundly alter cell shape. Platelets, for example, convert from a spherical to disk shape and extend filopodia (7), endothelial cells contract (8), neurons retract axons, and astrocytes resorb processes and flatten their cell bodies (9-11). These signals also regulate changes in actin-related cell motility observed in neurons (10), fibroblasts (12), and tumor cells (3). The morphological response is mediated by a key signaling pathway that uses serine͞ threonine kinases, G␣12͞13, RhoA, and myosin light chain kinase; actomyosin contraction ...

show abstract

Injury‐Related Factors and Conditions Down‐Regulate the Thrombin Receptor (PAR‐1) in a Human Neuronal Cell Line

Cited by 24 publications

References 87 publications

Role of Protease-Activated Receptor-1 in Brain Injury After Experimental Global Cerebral Ischemia

Role of Protease-Activated Receptor-1 in Brain Injury After Experimental Global Cerebral Ischemia

The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective?

Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton

Contact Info

Product

Resources

About