Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced glutathione (GSH) is an essential, multifunctional tripepetide that controls redox-sensitive cellular processes, but its regulation in the heart is poorly understood. The present study used a pharmocological model of GSH depletion to examine cellular mechanisms controlling cardiac GSH. Inhibition of GSH metabolism was elicited in normal rats by daily injections of buthionine sulfoximine (BSO), a blocker of gamma-glutamylcysteine synthetase, plus 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. After 3 d of BSO/BCNU treatment, intracellular [GSH] was measured in isolated-ventricular myocytes by fluorescence microscopy using the probe monochlorobimane. Basal [GSH] in left-ventricular myocytes from BSO/BCNU-treated rats (2.0 +/- 0.05 amol/microm(3), n = 146) was 50% less than control (4.0 +/- 0.13 amol/microm(3), n = 116; P < 0.05). Incubation of myocytes from BSO/BCNU rats with 0.1 microM insulin normalized [GSH] after a delay of 3-4 h (3.6 +/- 0.29 amol/microm(3), n = 66). This effect of insulin was blocked by pre-treating myocytes with cycloheximide. A protein tyrosine phosphatase inhibitor, bis-peroxovanadium-1,10-phenanthroline (bpV(phen), 1 microM), elicited a similar effect as insulin, while neither agent altered [GSH] in myocytes from control rats. Moreover, the effect of insulin and bpV(phen) to up-regulate GSH was blocked by inhibitors of PI 3-kinase (wortmannin, LY294002), MEK (PD98059) and p38 MAP kinases (SB203580). These data suggest that the insulin-signaling cascade regulates [GSH] in ventricular myocytes by a coordinated activation of PI 3-kinase and MAP kinase pathways. These signaling mechanisms may play essential roles in controlling intracellular redox state and normal function of cardiac myocytes.
 ...
PMID:Regulation of glutathione in cardiac myocytes. 1296 37

In mouse cerebellar granule neurons (CGNs) the marine neurotoxin domoic acid (DomA) induces neuronal cell death, either by apoptosis or by necrosis, depending on its concentration, with apoptotic damage predominating in response to low concentrations (100 nM). DomA-induced apoptosis is due to selective activation of AMPA/kainate receptors, and is mediated by DomA-induced oxidative stress, leading to mitochondrial dysfunction and activation of caspase-3. The p38 MAP kinase and the c-Jun NH2-terminal protein kinase (JNK) have been shown to be preferentially activated by oxidative stress. Here we report that DomA increases p38 MAP kinase and JNK phosphorylation, and that this effect is more pronounced in CGNs from Gclm (-/-) mice, which lack the modifier subunit of glutamate-cysteine ligase, have very low glutathione (GSH) levels, and are more sensitive to DomA-induced apoptosis than CGNs from wild-type mice. The increased phosphorylation of JNK and p38 kinase was paralleled by a decreased phosphorylation of Erk 1/2. The AMPA/kainate receptor antagonist NBQX, but not the NMDA receptor antagonist MK-801, prevents DomA-induced activation of p38 and JNK kinases. Several antioxidants (GSH ethyl ester, catalase and phenylbutylnitrone) also prevent DomA-induced phosphorylation of JNK and p38 MAP kinases. Inhibitors of p38 (SB203580) and of JNK (SP600125) antagonize DomA-induced apoptosis. These results indicate the importance of oxidative stress-activated JNK and p38 MAP kinase pathways in DomA-induced apoptosis in CGNs.
 ...
PMID:Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases. 1816 2