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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synaptosomes were isolated from rat and mouse brain and the effects of alcohol addition on calcium uptake were studied in vitro. Ethanol inhibited potassium-, glutamate-, and veratridine-stimulated calcium uptake. The inhibitory effects were obtained with concentrations of ethanol (less than or equal to 100 mM) which did not alter synaptosomal membrane potentials. Elevation of extrasynaptosomal calcium reduced the inhibitory effect of ethanol, resulting in apparently competitive kinetics. The inhibitory potencies of a series of alkanols were correlated with their membrane/buffer partition coefficients, implicating hydrophobic regions of the membrane as the site of alcohol action. However, not all nerve endings were equally sensitive to ethanol. Inhibition of potassium-stimulated calcium uptake was greater with synaptosomes prepared from cerebellum and striatum than with preparations from cortex or brain stem. In contrast, veratridine-stimulated calcium uptake (which is dependent upon sodium influx) was inhibited more strongly in cortex than in cerebellum. These results suggest that the calcium channels in cerebellum are more sensitive to ethanol than the calcium channels in cortex, whereas sodium channels in cortex are more sensitive than those in cerebellum.
Mol Pharmacol 1982 Jul
PMID:Alcohols and synaptosomal calcium transport. 712 53

1. Alcohols have been used as pharmacological tools to probe the nature of action-potential gates and channels. In this study, we examine the effects of alcohols upon activity patterns in Aplysia neurons. 2. Ethanol at concentrations of 0.4-0.6 M induces bursting pacemaker activity (BPA) in previously silent cells. The same effect is produced with 40-60 mM concentrations of butanol, suggesting that this induction is not due to osmotic effects. 3. Voltage-clamp measurements indicate that the induction of BPA is accompanied by the appearance of a negative-slope resistance (NSR) region in the steady-state current-voltage relationship of the cell. The induction of BPA and a NSR region in silent cells is antagonized by lowered temperatures. 4. Ethanol concentrations which produce BPA and a NSR region in silent cells abolish both of these normally present characteristics in endogenous bursters. This suggests that whatever membrane components are moved into optimal configuration for the expression of BPA in silent cells are shifted out of optimal configuration in endogenous bursters, by similar ethanol concentrations.
Cell Mol Neurobiol 1982 Sep
PMID:Effects of alcohols upon pacemaker activity in neurons of Aplysia californica. 715 3

Ethanol inhibits N-methyl-D-aspartate (NMDA) receptor-mediated responses at pharmacologically relevant concentrations, suggesting that inhibition of NMDA receptors may underlie some of the actions of ethanol in the central nervous system. We examined the ability of glycine to modulate ethanol inhibition of four recombinant heteromeric NMDA receptors (NR1a/NR2A through NR2D) expressed in Xenopus oocytes. Ethanol dose-response analysis revealed enhanced inhibitory efficacy of ethanol in the presence of subsaturating glycine concentrations at the NR1/NR2A, NR1/NR2C, and NR1/NR2D receptors. When assayed over a range of glycine concentrations, ethanol exhibited both glycine-reversible and glycine-independent inhibition of NMDA receptors. In contrast, ethanol inhibition of recombinant NMDA receptors was independent of NMDA concentration. Glycine reversal of ethanol inhibition suggested that ethanol might lower the affinity of glycine for the NMDA receptor and thereby decrease response magnitude. Consistent with this hypothesis, ethanol significantly reduced glycine affinity at NR1/NR2A and NR1/NR2C receptors. Evaluation of the glycine-independent component of ethanol inhibition demonstrated that in the presence of saturating concentrations of glycine, the NR1/NR2A and NR1/NR2B receptors were more sensitive to ethanol than the NR1/NR2C and NR1/NR2D receptors. Activation of the NR1/NR2D heteromers by NMDA and low concentrations of glycine elicited responses characterized by an initial peak followed by a lower-amplitude plateau response, which is consistent with glycine-sensitive desensitization as previously described for native NMDA receptors. In addition, nondesensitizing NR1/NR2B responses elicited in the presence of subsaturating concentrations of glycine were frequently converted into desensitizing responses by the addition of ethanol, an effect that was reversed with increasing glycine concentrations. The ability of ethanol to promote glycine-sensitive desensitization further suggests an interaction between glycine and ethanol inhibition of the NMDA receptor. Taken together, the results of the present report demonstrate that ethanol inhibition of NMDA receptors has both glycine-reversible and glycine-independent components, suggesting two distinct molecular mechanisms for ethanol inhibition of NMDA receptors.
Mol Pharmacol 1995 Oct
PMID:Glycine modulates ethanol inhibition of heteromeric N-methyl-D-aspartate receptors expressed in Xenopus oocytes. 747 99

The effect of the fungal toxin gliotoxin on the adherence and viability of mouse L929 cultured cells was examined. Gliotoxin at concentrations below 2 microM had no effect on cell function. The initial effect of exposure (6 h) resulted in the loss of cell adherence, with the non-adhered cells retaining viability. However, prolonged exposure (24 h) did not significantly enhance gliotoxin's effect on cell adherence, though the majority of non-adhered cells were found to have died by apoptosis, as confirmed from (i) electron microscopic examination and (ii) agarose gel electrophoresis of isolated DNA. The addition of foetal bovine serum to the culture medium had no effect on gliotoxin's activity. Ethanol (gliotoxin's solvent) had no effect on the assayed cell functions suggesting that the observed effects are due to gliotoxin alone. These results demonstrate for the first time that gliotoxin can cause apoptosis in cells of non-haematopoietic origins.
Biochem Mol Biol Int 1994 Jun
PMID:Gliotoxin induces apoptosis in mouse L929 fibroblast cells. 752 1

Free radical products have previously been detected in rodents after chronic feeding with an ethanol-containing, high-fat diet. The significance of reactive free radical formation in ethanol-induced hepatotoxicity has been difficult to assess because most rodent models exhibit only fatty liver. However, serious hepatic damage resembling clinical alcoholic liver injury (e.g., steatosis, inflammation, and necrosis) occurs in rats after continuous intragastric administration of an ethanol-containing, high-fat diet developed by Tsukamoto and French. Accordingly, rats treated with ethanol for at least 2 weeks using this protocol were administered the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone, and bile samples were collected. A six-line radical adduct spectrum was detected in the bile of ethanol-treated rats. A similar spectrum of lower intensity was detected with rats fed a high-fat diet without ethanol, but little or no radical adduct signal was detected with chow-fed animals. For both treatment groups, alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and extra ethanol were given acutely. Destruction of Kupffer cells by chronic treatment with GdCl3 decreased by about 50% the radical adduct formation in rats fed the ethanol-containing, high-fat diet. This radical species was largely ethanol derived, because addition of [13C]ethanol produced a 12-line spectrum, indicating the formation of alpha-hydroxyethyl radical. Ethanol treatment also caused hypoxia (detected on the liver surface in vivo with oxygen electrodes), which was reflected in a dose-dependent decrease in oxygen tension with ethanol. The effect was blocked by GdCl3. Hepatic damage detected by histology was prevalent in ethanol-treated rats but only mild fatty liver was observed in high-fat diet-fed controls. GdCl3 treatment eliminated hepatic damage due to high-fat and ethanol diets, and when all groups were compared a significant correlation between liver injury and radical adduct signal was observed. Thus, free radical formation in ethanol-treated rats has been detected for the first time in a model that exhibits injury characteristic of human alcoholic injury, and signal intensity correlates with hepatotoxicity. Moreover, the decrease in both free radical formation and hepatic damage produced by GdCl3 implicates Kupffer cells in the development of alcoholic liver injury. This important pathophysiological process may involve direct production of reactive oxygen species or indirect actions of mediators on parenchymal cells.
Mol Pharmacol 1995 May
PMID:Free radical adducts in the bile of rats treated chronically with intragastric alcohol: inhibition by destruction of Kupffer cells. 774 69

Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.
Mol Aspects Med 1994
PMID:Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. 775 31

Ethanol-hypersensitive strains (ets mutants), unable to grow on media containing 6% ethanol, were isolated from a sample of mutagenized Schizosaccharomyces pombe wild-type cells. Genetic analysis of these ets strains demonstrated that the ets phenotype is associated with mutations in a large set of genes, including cell division cycle (cdc) genes, largely non-overlapping with the set represented by the temperature conditional method; accordingly, we isolated some ets non-ts cdc- mutants, which may identify novel essential genes required for regulation of the S. pombe cell cycle. Conversely, seven well characterized ts cdc- mutants were tested for their ethanol sensitivity; among them, cdc1-7 and cdc13-117 exhibited a tight ets phenotype. Ethanol sensitivity was also tested in strains bearing different alleles of the cdc2 gene, and we found that some of them were ets, but others were non-ets; thus, ethanol hypersensitivity is an allele-specific phenotype. Based on the single base changes found in each particular allele of the cdc2 gene, it is shown that a single amino acid substitution in the p34cdc2 gene product can produce this ets phenotype, and that ethanol hypersensitivity is probably due to the influence of this alcohol on the secondary and/or tertiary structure of the target protein. Ethanol-dependent (etd) mutants were also identified as mutants that can only be propagated on ethanol-containing media. This novel type of conditional phenotype also covers many unrelated genes. One of these etd mutants, etd1-1, was further characterized because of the lethal cdc- phenotype of the mutant cells under restrictive conditions (absence of ethanol). The isolation of extragenic suppressors of etd1-1, and the complementation cloning of a DNA fragment encompassing the etd1+ wild-type gene (or an extragenic multicopy suppressor) demonstrate that current genetic techniques may be applied to mutants isolated by using ethanol as a selective agent.
Mol Gen Genet 1994 Oct 17
PMID:Ethanol-hypersensitive and ethanol-dependent cdc- mutants in Schizosaccharomyces pombe. 784 61

Differential Northern blot hybridization was used as a screening tool to identify mRNAs that respond quantitatively to the induction of ethanol dependence. Adult male rats were treated with repeated, high doses of ethanol for 4 consecutive days. This regimen resulted in the development of tolerance and dependence upon ethanol. RNA isolated from the ethanol-dependent rat brains was used to construct a cDNA library. One cDNA was identified that hybridized to a mRNA which increased in rat brain during the ethanol treatment. Sequence analysis of the cDNA indicated that it recognized a mRNA in rat brain which was very similar to that which encodes the 18 kDa subunit of canine signal peptidase. The rat signal peptidase mRNA was observed to increase in brain nearly 2-fold within 48 h after the initiation of ethanol treatment. Ethanol did not significantly alter beta-actin mRNA levels during the treatment period. These results support the existence of an ethanol-responsive signal peptidase mRNA in rat brain.
Mol Cell Biochem 1994 Oct 12
PMID:Induction of ethanol dependence increases signal peptidase mRNA levels in rat brain. 785 39

Ethanol inhibits [125I]calmodulin binding to synaptic plasma membranes from rat brain, and this inhibition is correlated in a concentration-dependent manner with the increase of membrane fluidity, as determined by diphenylhexatriene fluorescence polarization. Moreover, several short-chain alcohols that increase membrane fluidity are also effective inhibitors of [125I]calmodulin binding. These data support the notion that ethanol inhibits calmodulin binding by increasing lipid fluidity of the synaptic membranes.
Brain Res Mol Brain Res 1994 Dec
PMID:Correlation between [125I]calmodulin binding and lipid fluidity in synaptic plasma membranes: effects of ethanol and other short-chain alcohols. 789 20

Ribonuclease II is a processive 3' exoribonuclease in Escherichia coli. It degraded substrates with 3'-OH or 2',3'-cyclicP ends slightly faster than those with 3'-P or 2'-P groups with a turnover number of approximately 70 nt/s at 37 degrees C. RNase II does not degrade DNA but the specificity for ribose was not for the cleavage bond but rather for ribo-bonds three to four nucleotides (nt) upstream, which could explain why the limit digest is a dimer. Oligonucleotides (oligos) of deoxy(C) were reversible competitive inhibitors of the enzyme and indicated a strong upstream binding site (approximately 15 to 27 nt from the 3' end). These oligos could protect RNase II from inactivation by heat or from diethylpyrocarbonate, an agent that preferentially reacts with His residues. Compared to oligo(dC), oligos of (dA) were at least 500 times less effective inhibitors of RNase II. Using mixed oligo(dAdC) inhibitors, an obligatory 3' to 5' direction of binding into the catalytic site was shown. From the reaction kinetics of RNase II under different conditions it was concluded that the enzyme recognition differs for poly(A), poly(C) and poly(U). Poly(C) was degraded more slowly than poly(A) or poly(U) with a 3.5 times slower Vmax, while rate differences between small oligos were extreme; oligo(A)7 was degraded > 100 times faster than oligo(C)7. Ethanol, which weakens hydrophobic interactions, increased the reaction velocity of poly(C) to that of poly(A) and poly(U). It had no effect on the reaction velocities of poly(A) or poly(U), but decreased the binding of poly(A) markedly. Oligo(A) was bound more strongly to a hydrophobic column than was oligo(C). Salt, which affects charge interactions, decreased the binding affinity and/or association rate of poly(C) to RNase II, had a lesser effect on poly(U), but the reactions of poly(A) were unaffected even in much higher concentrations of salt. A clue to the slower reaction velocity of poly(C) was shown when the reaction intermediates were viewed by PAGE. At lower temperatures of reaction (< 25 degrees C), there were more intense bands separated by discrete distances of approximately 12 nt during the degradation of poly(C) by RNase II. Chase experiments showed that these stops were accounted for by dissociation of poly(C) from the enzyme. They were not seen when poly(C) was degraded at 37 degrees C or degraded in the presence of 20% ethanol at any temperatures, nor were they seen when poly(A) or poly(U) was degraded even at low temperatures.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1994 Nov 11
PMID:The processive reaction mechanism of ribonuclease II. 796 9


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