Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate whether the phosphorylation of p38 in cerebral ischemia occurs via angiotensin II receptor type 1a (AT1a), we examined the time course of phosphorylation of p38 and proline-rich tyrosine kinase 2 in AT1a knock-out mouse striatal neurons during middle cerebral artery occlusion (MCAO) and reperfusion. Phosphorylated-p38 was observed after 2 h and 5 h of reperfusion after 1 h of MCAO in C57/B6 mice and AT1a knock out mice, respectively. We demonstrated a delay of phosphorylation of p38 in the reperfusion model of the AT1a knock-out mouse, and detected microglia in the striatum on the ischemic side that were phosphorylated-p38-positive after 71 h of reperfusion in both animals. However, there was no association between AT1a and delayed neuronal cell death, or between AT1a and activation of caspase-9 in cerebral ischemia/reperfusion.
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PMID:Delayed phosphorylation of p38 mitogen-activated protein kinase in the AT1a knock-out mouse striatal neurons during middle cerebral artery occlusion and reperfusion. 1267 31

Cerebral ischemia induces rapid efflux of glutamate into the extracellular space contributing to excessive activation of glutamate receptors in postsynaptic cells, particularly N-methyl-D-aspartate (NMDA) receptors, which triggers the neuron lesion through calcium overload. Our studies indicated that cerebral ischemia stimulated the rapid activation of nonreceptor tyrosine kinases proline-rich tyrosine kinase 2 (Pyk2) and Src and the binding to Pyk2 activated the latter. Pyk2 activation significantly depends on the increase of the intracellular calcium level; blockage of both calcium ion channel NMDA receptors and L-type voltage-gated Ca2+ channel (L-VGCC), respectively, could effectively inhibit phosphorylation of Pyk2 in early ischemia episodes. Moreover, pretreatment with the protein kinase C inhibitor (chelerythrine chloride) reduced the ischemia-induced activation of Pyk2. Noticeably, CaMKII, a family of calcium/calmodulin-dependent kinases, also may be involved in the regulation of Pyk2 activity because its inhibitor KN62 attenuated Pyk2 phosphorylation during ischemia. Together with previous studies, these results indicate that calcium influx elicited by active NMDA receptors and L-VGCC triggers the Pyk2-Src signaling pathway mediated by PKC, which aggravates cerebral ischemia lesions through up-regulating the function of NMDA receptors after the onset of ischemia, and also could be regulated partly by CaM-dependent kinases like CaMKII.
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PMID:N-methyl-D-aspartate receptor and L-type voltage-gated Ca2+ channel activation mediate proline-rich tyrosine kinase 2 phosphorylation during cerebral ischemia in rats. 1473 60

Previous studies have demonstrated that activation of proline-rich tyrosine kinase 2 (PYK2) in cerebral ischemia is involved in the modulation of N-methyl-d-aspartate-type (NMDA) glutamate receptor activity and Ca(2+) dynamics, resulting in ischemic neuron death ultimately. A number of reports indicate that PYK2 is a redox sensitive kinase that must be activated by an estrogen-induced reactive oxygen species (ROS). However, the mechanism of PYK2 activation remains incompletely illustrated. Accumulating attention is focused on nitric oxide (NO, a free radical) which plays a critical role in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. Here we reported that PYK2 over-expressed in human embryonic kidney (HEK293) cells was S-nitrosylated (forming SNO-PYK2) by reacting with GSNO, an exogenous NO donor, at one critical cysteine residue (Cys534) with a biotin switch assay. Moreover, our results showed that S-nitrosylation and phosphorylation of PYK2 over-expressed in SH-SY5Y cells was significantly increased after oxygen-glucose deprivation (OGD). We further investigated whether the activation (phosphorylation) of PYK2 was associated with S-nitrosylation following SH-SY5Y cells OGD. Our results showed that the cysteine534 residue (site of S-nitrosylation) mutant PYK2 over-expressed in SH-SY5Y cells diminished S-nitrosylation of PYK2 and inhibited its phosphorylation induced by OGD. In addition, overexpression of the mutant PYK2 protein could prevent nuclear accumulation and abrogate neuronal cell death compared to wild type PYK2 in SH-SY5Y cells induced by OGD. These data suggest that the activation of PYK2 following OGD may be modulated by S-nitrosylation, which provides a new avenue for stroke therapy by targeting the post-translational modification machinery.
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PMID:S-Nitrosylation of proline-rich tyrosine kinase 2 involves its activation induced by oxygen-glucose deprivation. 2592 87

Protein tyrosine phosphorylation is one of the primary modes of regulation of N-methyl-d-aspartate (NMDA) receptors. The non-receptor tyrosine kinases are one of the two types of protein tyrosine kinases that are involved in this process. The overactivation of NMDA receptors is a primary reason for neuron death following cerebral ischemia. Many studies have illustrated the important role of non-receptor tyrosine kinases in ischemia insults. This review introduces the roles of Src, Fyn, focal adhesion kinase, and proline-rich tyrosine kinase 2 in the excitotoxicity induced by the overactivation of NMDA receptors following cerebral ischemia.
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PMID:The role of non-receptor protein tyrosine kinases in the excitotoxicity induced by the overactivation of NMDA receptors. 2654 Feb 20

Mitochondrial dysfunction caused by Ca2+ overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca2+ uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca2+ uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress-induced cellular apoptosis. In this study, we explored the role of the Pyk2/MCU pathway in the ischemic brain following a stroke injury. We found that the Pyk2/MCU pathway is activated in a rat cerebral ischemia model, and is responsible for mitochondrial dysfunction and neuronal apoptosis. Inhibiting the Pyk2/MCU pathway with a Pyk2 inhibitor (PF-431396) prevented mitochondrial Ca2+ overload, mitochondrial injury, proapoptotic protein release, and cell death. Interestingly, human urinary kallidinogenase (HUK) alleviated neuronal ischemic injury by inhibiting the Pyk2/MCU pathway, suggesting that the Pyk2/MCU pathway may be a protective target for ischemic stroke treatment.
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PMID:The Pyk2/MCU pathway in the rat middle cerebral artery occlusion model of ischemic stroke. 2891 71