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)

As an approach to understanding the molecular basis of the pathophysiology of cerebral ischemia, we examined qualitative and quantitative changes in pertussis toxin substrates, Gi1 and G0, in the membrane of rat cerebral cortex after decapitation. Within 1 min after decapitation, the extent of pertussis toxin-catalyzed [32P]ADP ribosylation of the G proteins in the cerebral cortex membrane was significantly decreased and the magnitude of the decrease became slightly larger upon further incubation of the decapitated brain. Addition of guanine nucleotides, GTP and GDP, or the purified beta gamma subunits of transducin to the membranes of control and ischemic cerebral cortex stimulated [32P]ADP ribosylation of the G proteins. The stimulation of [32P]ADP ribosylation in the control situation by guanine nucleotides was almost to the same extent as that in ischemia. However, the stimulation by transducin beta gamma subunits was different; the control stimulation was greater than that in ischemia. In immunoblots probed with antibodies against Gi1 alpha, G0 alpha, and T beta, the immunoreactivity of the corresponding proteins in ischemia was similar to that in control, suggesting that the amounts of G proteins were not changed in ischemia. These results suggest that ischemia accelerates the dissociation of alpha-GDP-beta gamma to alpha-GDP and free beta gamma and causes the denaturation of the dissociated alpha-GDP, thereby decreasing [32P]ADP ribosylation.
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PMID:Ischemia of rat brain decreases pertussis toxin-catalyzed [32P]ADP ribosylation of GTP-binding proteins (Gi1 and G0) in membranes. 189 6

Rats were subjected to the standard four-vessel occlusion model of cerebral transient ischaemia (vertebral and carotid arteries) for 15 and 30 min. After a 30 min recirculation period, protein synthesis rate, initiation factor 2 (eIF-2) and guanine nucleotide exchange factor (GEF) activities, and the level of phosphorylation of the alpha subunit of eIF-2 (eIF-2 alpha) were determined in the neocortex region of the brain from sham-operated controls and ischaemic animals. Following reversible cerebral ischaemia, the protein synthesis rate, as measured in a cell-free system, was significantly inhibited (70%) in the ischaemic animals. eIF-2 activity, as measured by its ability to form a ternary complex, also decrease parallel to the decrease in protein synthesis. As eIF-2 activity was assayed in the presence of Mg2+ and GTP-regenerating capacity, the decrease in ternary-complex formation indicated the possible impairment of GEF activity. Since phosphorylated eIF-2 [eIF-2(alpha P)] is a powerful inhibitor of GEF, the levels of phosphorylated eIF-2 alpha were determined, and an increase from 7% phosphorylation in sham control rats to 20% phosphorylation in 15 min and 29% phosphorylation in 30 min in ischaemic rats was observed, providing evidence for a tight correlation of phosphorylation of eIF-2 alpha and inhibition of protein synthesis. Moreover, GEF activity measured in the GDP-exchange assay was in fact inhibited in the ischaemic animals, proving that protein synthesis is impaired by the presence of eIF-2(alpha P), which blocks eIF-2 recycling.
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PMID:Phosphorylation of the alpha subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat. 809 84

Neuronal protein synthesis is severely depressed following stress such as heat-shock, hypoxia, and hypoglycemia. Following reversible cerebral ischemia, protein synthesis is transiently inhibited in ischemia-resistant areas, but persistently depressed in vulnerable brain regions. Eukaryotic initiation factor 2 (eIF-2) activity, that is, the formation of the ternary complex eIF-2.GTP.initiator 35S-Met-tRNA, a rate-limiting step in the initiation of cellular protein synthesis, was studied in the rat brain during and following 15 min of transient global cerebral ischemia. At 30 min and 1 hr of reperfusion, a general decrease of eIF-2 activity by approximately 50% was seen in the postmitochondrial supernatant (PMS). In the relatively resistant neocortex and CA3 region of the hippocampus, the eIF-2 activity returns to control levels at 6 hr of reperfusion, but remains depressed in the vulnerable striatum and the CA1 region. Similarly, the activity of the guanine nucleotide exchange factor (GEF), which catalyzes the exchange of GTP for GDP bound to eIF-2, a crucial step for the continued formation of the ternary complex, is transiently reduced in neocortex but persistently depressed in striatum. The postischemic decrease in eIF-2 activity is further attenuated by agarose-bound alkaline phosphatase, and mixing experiments revealed that a vanadate-sensitive phosphatase may be responsible for the depression. Addition of partially purified GEF to PMS from postischemic neocortex restored eIF-2 activity to control levels. We conclude that ischemia alters the balance between phosphorylation and dephosphorylation reactions, leading to an inhibition of GEF and a depression of ternary complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stress-induced inhibition of protein synthesis initiation: modulation of initiation factor 2 and guanine nucleotide exchange factor activities following transient cerebral ischemia in the rat. 847 77

The intracellular signaling mechanisms that couple transient cerebral ischemia to cell death and neuroprotective mechanisms provide potential therapeutic targets for cardiac arrest. Protein phosphatase (PP)-1 is a major serine/threonine phosphatase that interacts with and dephosphorylates critical regulators of energy metabolism, ionic balance, and apoptosis. We report here that PP-1(I), a major regulated form of PP-1, is activated in brain by approximately twofold in vivo following cardiac arrest and resuscitation in a clinically relevant pig model of transient global cerebral ischemia and reperfusion. PP-1(I) purified to near homogeneity from either control or ischemic pig brain consisted of the PP-1 catalytic subunit, the inhibitor-2 regulatory subunit, as well as the novel constituents 14-3-3gamma, Rab GDP dissociation protein beta, PFTAIRE kinase, and C-TAK1 kinase. PP-1(I) purified from ischemic brain contained significantly less 14-3-3gamma than PP-1(I) purified from control brain, and purified 14-3-3gamma directly inhibited the catalytic subunit of PP-1 and reconstituted PP-1(I). These findings suggest that activation of brain PP-1(I) following global cerebral ischemia in vivo involves dissociation of 14-3-3gamma, a novel inhibitory modulator of PP-1(I). This identifies modulation of PP-1(I) by 14-3-3 in global cerebral ischemia as a potential signaling mechanism-based approach to neuroprotection.
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PMID:Activation of brain protein phosphatase-1(I) following cardiac arrest and resuscitation involving an interaction with 14-3-3 gamma. 1828 17