UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ryanodine receptors (RyRs) are intracellular channels that regulate the release of Ca2+ from the endoplasmic reticulum of many cell types. The RyRs are physically associated with FK506-binding proteins (FKBPs); immunophilins, with cis-trans peptidyl-prolyl isomerase activity. FKBP12 copurifies with RyR1 (skeletal isoform) and modulates its gating. A different form of FKBP with a slightly higher molecular weight copurifies with RyR2 (cardiac isoform). Previous studies have demonstrated that FKBP stablizes gating of the skeletal Ca(2+)-release channel. In the present study, we measured the activity of cardiac RyRs incorporated into planar lipid bilayers to show that rapamycin, a drug that inhibits the prolyl isomerase activity of FKBP and dissociates FKBP from the RyR, increases the open probability and reduces the current amplitude of cardiac muscle Ca(2+)-release channels. These experiments show for the first time that submicromolar concentrations of rapamycin can alter channel function. Our results provide support for the hypotheses that FKBP functionally associates with the RyR and that the immunosuppressant drug, rapamycin, alters the function of both cardiac and skeletal muscle isoforms of the Ca(2+)-release channel. Our findings suggest that FKBP-dependent modulation of channel function may be generally applicable to all members of the intracellular Ca(2+)-release channel family and that FKBPs may play important regulatory roles in many cell processes, ranging from long-term depression in neurons to contractility in cardiomyocytes.
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PMID:Effects of rapamycin on ryanodine receptor/Ca(2+)-release channels from cardiac muscle. 863 49

1. The induction of long-term potentiation (LTP) was investigated in the rat dentate gyrus in the presence of ryanodine, an agent which is known to selectively bind to the ryanodine receptor (RyR) Ca2+ channels which regulate Ca2+ release from intracellular Ca2+ stores. 2. In control media, high frequency stimulation (HFS) induced LTP, and prolonged low frequency stimulation (LFS) induced long-term depression (LTD), of field excitatory postsynaptic potentials (EPSPs) and patch clamped excitatory postsynaptic currents (EPSCs). 3. In the presence of ryanodine, at a threshold concentration of about 1 microM, HFS-induced LTP was inhibited, whereas LFS (5 Hz, 900 pulses) now induced LTP. 4. The N-methyl-D-aspartate receptor (NMDAR) antagonist D-2-amino-phosphonopentanoate (D-AP5), at both 50 and 200 microM, did not prevent the induction of LTP by 5 Hz LFS in the presence of ryanodine. This demonstrates the NMDAR independence of LTP induction in the presence of ryanodine. Furthermore, D AP5 reversed the block of HFS-induced LTP by ryanodine. 5. The induction of LTP by 5 Hz LFS in the presence of ryanodine was blocked by lowering extracellular Ca2+, or by rapidly buffering intracellular Ca2+ to very low levels with BAPTA. 6. The induction of LTP by 5 Hz LFS was inhibited by the L-type voltage-gated Ca2+ channel blocker nifedipine, and also by Ni2+ a commonly used T type voltage-gated Ca2+ channel blocker. 7. The 5 Hz LFS-induced LTP in the presence of ryanodine was inhibited by the metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl 4-carboxyphenylglycine (MCPG). 8. The 5 Hz LFS-induced LTP in the presence of ryanodine was blocked by Ruthenium Red, an agent known to block RyR channel opening, and also by thapsigargin, an agent known to block-ATP-dependent Ca2+ uptake into endoplasmic reticulum. 9. The results of the present studies emphasize the importance of intracellular Ca2+ stores in the induction of LTP.
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PMID:Ryanodine produces a low frequency stimulation-induced NMDA receptor-independent long-term potentiation in the rat dentate gyrus in vitro. 888 81

Incubation of reticular membranes with Fe(2+)-EDTA and H2O2 plus Fe(2+)-EDTA at 37 degrees C for 30 min led to the loss of membrane's efficiency to sequester Ca2+ to 21.8% and 3.6% of control values, respectively. The incubation of microsomes with Fe(2+)-EDTA and H2O2 plus Fe(2+)-EDTA also caused decrease of Ca(2+)-ATPase activity; to 44.9% and 44.4% (measured under the same conditions as Ca(2+)-uptake) or to 79.6% and 62.1% (uncoupled from Ca2+ transport by detergent). In addition, incubation of membranes with Fe(2+)-EDTA and H2O2 plus Fe(2+)-EDTA at 37 degrees C for 30 min led to the increase of Ca2+ permeability to 125.1% and 124.2%, respectively. Preincubation of membranes with membrane-soluble antioxidants (U-74500A, U-83836E, t-butyl hydroxytoluene and stobadine) protected the reticular membranes against depression of Ca2+ uptake values and Ca(2+)-ATPase inhibition in a dose and an antioxidant nature dependent manner. Our results indicate that both processes, Ca(2+)-ATPase inhibition and increase of endoplasmic reticulum membrane Ca2+ permeability, participate in the lipid peroxidation induced loss of membrane's efficiency to sequester Ca2+.
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PMID:Lipid peroxidation both inhibits Ca(2+)-ATPase and increases Ca2+ permeability of endoplasmic reticulum membrane. 911 26

The aim of the present study is a morphometric, ultrastructural evaluation of satellite cells (SC) derived from the soleus muscle (SOL) of rats exposed to conditions of hypokinesia for a period of 7 or 21 days. Qualitative and quantitative analysis of 320 electron micrographs of SC from each group was carried out. After 7 and 21 days of immobilization, profiles of the SC, in contrast to the control group, had a lower mean surface area, had a cylindrical shape, and exhibited more folded membrane. Analysis of electron micrographs of SC showed that after immobilization, a lower number of SC contained profiles of mitochondria, rough endoplasmic reticulum (RER), and Golgi. Volume fractions of RER were twofold lower after 7 days of hypokinesia and fivefold lower after 21 days compared with the control group. The SC of SOL of rats subjected to hypokinesia differed from the control group by a markedly decreased number of ribosomes and RER profiles. After 21 days of immobilization the ultrastructural characteristics of SC were typical for cells in an inactive state showing various degrees of degeneration. The results of our study presented here permit the conclusion that 21 days of hypokinesia induce a depression of SC activity, whereas subtle changes in SC appear only after 7 days of immobilization.
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PMID:Quantitative ultrastructural evaluation of satellite cells in soleus muscle from rats kept in hypokinesia. 920 5

To evaluate the relationship between cardiovascular injury and the pathological significance of endothelial constitutive nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) in endotoxic shock, Wistar rats were injected intraperitoneally with 10 mg/kg Escherichia coli endotoxin and the resulting cardiovascular changes observed using immunohistochemistry, immunoelectron microscopy, the reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization at 4, 6, 8 and 10 h after endotoxin administration. Immunohistochemical and electron microscopic observations showed that ecNOS was localized in the cytoplasmic vesicles and rough endoplasmic reticulum of the endothelium of coronary arteries and intermyocardial capillaries in both control and endotoxin-treated rats. iNOS was localized in the cytoplasmic vesicles and endoplasmic reticulum of vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes after endotoxin administration. The RT-PCR study confirmed the expression of ecNOS and iNOS mRNA in the heart tissues of all animals including controls. In situ hybridization showed that ecNOS mRNA was expressed in the cytoplasm of vascular endothelial cells in control and endotoxin-treated rats. After endotoxin administration, iNOS mRNA was strongly expressed in vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes and a small number of macrophages. Bacterial lipopoly-saccharide induces rapid release of nitric oxide in the microvasculature and cardiomyocytes resulting in the depression of cardiomyocyte contraction. These findings may describe the cardiac response after endotoxin treatment.
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PMID:Differential distribution of ecNOS and iNOS mRNA in rat heart after endotoxin administration. 929 May 78

Mutations in the presenilin-1 (PS-1) gene account for approximately 50% of the cases of autosomal dominant, early onset, inherited forms of Alzheimer's disease (AD). PS-1 is an integral membrane protein expressed in neurons and is localized primarily in the endoplasmic reticulum (ER). PS-1 mutations may promote neuronal degeneration by altering the processing of the beta-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid beta-peptide (Abeta) and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPPalpha). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPPalpha activated the transcription factor NF-kappaB and prevented apoptosis induced by Abeta. Treatment of cells with kappaB decoy DNA blocked the antiapoptotic action of sAPPalpha, demonstrating the requirement for NF-kappaB activation in the cytoprotective action of sAPPalpha. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-kappaB activity following exposure to Abeta, which was characterized by enhanced early activation of NF-kappaB followed by a prolonged depression of activity. Blockade of NF-kappaB activity in cells expressing mutant PS-1 by kappaB decoy DNA was associated with enhanced Abeta-induced increases of [Ca2+]i and mitochondrial dysfunction. Treatment of cells with sAPPalpha stabilized [Ca2+]i and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-kappaB. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigargin induced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal role for ER calcium release in the proapoptotic action of mutant PS-1. Finally, a role for NF-kappaB in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPPalpha prevents thapsigargin-induced apoptosis, an effect blocked by kappaB decoy DNA. We conclude that sAPPalpha stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappaB. The data further suggest that PS-1 mutations result in aberrant NF-kappaB regulation that may render neurons vulnerable to apoptosis.
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PMID:Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaB and stabilization of calcium homeostasis. 957 87

The role of mitochondrial dysfunction in alterations of calcium signalling in primary sensory neurons has been studied in mice with streptozotocin-induced and genetically predisposed diabetes mellitus before and after additional treatment with insulin infusions. Cytosolic calcium transients triggered by membrane depolarization were measured using a membrane-permeable form of fluorescent indicator indo-1, and their changes after application of mitochondrial uncoupler carbonyl cyanide m-chlorphenylhydrazone were compared in cells of control and diabetic animals. Considerable prolongation of residual elevation of cytosolic calcium after termination of membrane depolarization was observed in diabetic mice, which was expressed mainly in small-sized (nociceptive) neurons. This correlated with the level of hyperglycemia, which was maximal in cells from streptozotocin-treated mice. Insulin partly reversed these changes. Carbonyl cyanide m-chlorophenylhydrazone application to neurons of control mice enlarged the peak of calcium transients and decreased residual calcium elevations, indicating that mitochondria in physiological conditions participate in shaping of these transients by diminishing their peak due to rapid uptake of calcium ions and by prolonging them due to subsequent slow calcium release back into the cytosol. Depression of the calcium accumulating function of mitochondria by carbonyl cyanide m-chlorophenylhydrazone eliminated these changes. The prolonged residual elevation of cytosolic calcium characteristic for neurons of diabetic animals was also eliminated by carbonyl cyanide m-chlorophenylhydrazone, confirming the suggestion that such elevation is determined mainly by mitochondrial dysfunction, the latter being dependent on the level of hyperglycemia. Predominant expression of such changes in small-sized neurons can be explained by the absence in them of effective calcium-buffering by the endoplasmic reticulum. Possible role of the described calcium signalling changes in the origin of neuropathic syndromes is discussed.
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PMID:Role of mitochondrial dysfunction in calcium signalling alterations in dorsal root ganglion neurons of mice with experimentally-induced diabetes. 1021 57

To evaluate the role in synaptic plasticity of ryanodine receptor type 3 (RyR3), which is normally enriched in hippocampal area CA1, we generated RyR3-deficient mice. Mutant mice exhibited facilitated CA1 long-term potentiation (LTP) induced by short tetanus (100 Hz, 100 ms) stimulation. Unlike LTP in wild-type mice, this LTP was not blocked bythe NMDA receptor antagonist D-AP5 but was partially dependent on L-type voltage-dependent Ca2+ channels (VDCCs) and metabotropic glutamate receptors (mGluRs). Long-term depression (LTD) was not induced in RyR3-deficient mice. RyR3-deficient mice also exhibited improved spatial learning on a Morris water maze task. These results suggest that in wild-type mice, in contrast to the excitatory role of Ca2+ influx, RyR3-mediated intracellular Ca2+ ([Ca2+]i) release from endoplasmic reticulum (ER) may inhibit hippocampal LTP and spatial learning.
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PMID:Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3. 1059 20

The high energy requirements compared to the low energy reserves render the brain particularly vulnerable to hypoxic conditions. To protect the brain against hypoxia, powerful cerebrovascular regulatory systems assure an increase of blood flow to compensate for the reduced arterial oxygen content. This system is so efficient that during respiratory hypoxia brain metabolism is little disturbed as long as cardiac function does not fail. Only with declining blood pressure cerebral blood flow also declines, and brain energy metabolism rapidly collapses. Under experimental conditions, oxygen delivery to the brain is therefore more readily impaired by reducing blood flow in the first place, e.g. by occluding a supplying brain artery. With declining flow values metabolic and electrophysiological functions stepwise disappear according to the threshold concept of brain ischemia: first the most complex functions such as protein synthesis or the spontaneous electrical activity are suppressed, followed at much lower flow values by the breakdown of energy state and the depolarisation of cell membranes. The tissue supplied at a flow range between functional impairment and the suppression of vital functions has been called penumbra to characterize its potential revivability, provided oxygen supply is resumed. Besides its immediate effects, hypoxia causes delayed functional and metabolic disturbances which may even progress to cell death. The brain regions most sensitive to this type of injury are parts of the hippocampus, the dorsolateral caudate nucleus and the reticular nucleus of thalamus. Mechanisms contributing to delayed injury include coupling disturbances between brain function and blood flow, glutamate-propagated functional disturbances such as spreading depression, free radical mediated changes, disturbances of signal transduction pathways and complex abnormalities in the genomic expression patterns leading, in the worst case, to programmed cell death. A key mechanism in this complex stress response is the disturbed calcium homoeostasis of the endoplasmic reticulum which, among others, leads to the inhibition of protein synthesis at the translational level. Modulations of these pathological interactions are a major area of current ischemia research.
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PMID:The hypoxic brain. Insights from ischemia research. 1063

Interstitial ionic shifts that accompany ouabain-induced spreading depression (SD) were studied in rat hippocampal and cortical slices in the presence and absence of extracellular Ca(2+). A double-barreled ion-selective microelectrode specific for H(+), K(+), Na(+), or Ca(2+) was placed in the CA1 stratum radiatum or midcortical layer. Superfusion of 100 microM ouabain caused a rapid, negative, interstitial voltage shift (2-10 mV) after 3-5 min. The negativity was accompanied by a rapid alkaline transient followed by prolonged acidosis. In media containing 3 mM Ca(2+), the alkalosis induced by ouabain averaged 0.07 +/- 0.01 unit pH. In media with no added Ca(2+) and 2 mM EGTA, the alkaline shift was not significantly different (0.09 +/- 0.02 unit pH). The alkaline transient was unaffected by inhibiting Na(+)-H(+) exchange with ethylisopropylamiloride (EIPA) or by blocking endoplasmic reticulum Ca(2+) uptake with thapsigargin or cyclopiazonic acid. Alkaline transients were also observed in Ca(2+)-free media when SD was induced by microinjecting high K(+). The late acidification accompanying ouabain-induced SD was significantly reduced in Ca(2+)-free media and in solutions containing EIPA. The ouabain-induced SD was associated with a rapid but relatively modest increase in [K(+)](o). In the presence of 3 mM external Ca(2+), the mean peak elevation of [K(+)](o) was 12 +/- 0.62 mM. In Ca(2+)-free media, the elevation of [K(+)](o) had a more gradual onset and reached a significantly larger peak value, which averaged 22 +/- 1.1 mM. The decrease in [Na(+)](o) that accompanied ouabain-induced SD was somewhat greater. The [Na(+)](o) decreased by averages of 40 +/- 7 and 33 +/- 3 mM in Ca(2+) and Ca(2+)-free media, respectively. In media containing 1.2 mM Ca(2+), ouabain-induced SD was associated with a substantial decrease in [Ca(2+)](o) that averaged 0.73 +/- 0. 07 mM. These data demonstrate that in comparison with conventional SD, ouabain-induced SD exhibits ion shifts that are qualitatively similar but quantitatively diminished. The presence of external Ca(2+) can modulate the phenomenon but is irrelevant to the generation of the SD and its accompanying alkaline pH transient. Significance of these results is discussed in reference to the propagation of SD and the generation of interstitial pH changes.
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PMID:Extracellular pH changes and accompanying cation shifts during ouabain-induced spreading depression. 1071 61

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