Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Moderate alcohol consumption protects against coronary heart disease by unclear mechanisms. We tested whether chronic ethanol preconditioning requires activation of mitochondrial K(ATP)channels. Rats were fed 18% (v/v) ethanol in drinking water for 10 months. Blood alcohol levels at sacrifice were 3 mmol/l (0.015 gram percent). Isolated crystalloid-perfused hearts were subjected to global ischemia and reperfusion on a modified Langendorff apparatus. Prior alcohol exposure doubled the recovery of LVDP during reperfusion (45+/-5%v 20+/-3% of baseline for controls, n=6, P<0.01) and blunted the rise in LVEDP (3.5+/-0.5 v 5.5+/-0.4 times baseline for controls, n=6, P<0.01). Ethanol feeding also reduced creatine kinase release during reperfusion. Inhibition of mitochondrial K(ATP)channels with 5-hydroxydecanoate had no effect on baseline LVDP, LVEDP, or coronary flow but abolished the beneficial effects of alcohol on LV contractile recovery and myocyte necrosis. We conclude that mitochondrial K(ATP)channel activity is required for chronic ethanol-induced protection.
J Mol Cell Cardiol 2000 Nov
PMID:Chronic ethanol-induced myocardial protection requires activation of mitochondrial K(ATP) channels. 1104 Jan 12

Ethanol induces profound alterations in the neuronal signaling systems, including the calcium (Ca(2+)) signaling. Prolonged exposure to ethanol evokes adaptive changes in the affected systems as they strive to restore the normal neuronal function. We investigated the involvement of calmodulin (CaM) genes, coding for the major mediator protein of intracellular Ca(2+) signals, in these adaptive processes at the mRNA level. The changes induced in the regional abundances of the CaM I, II, and III mRNA classes by chronic ethanol treatment and withdrawal were examined by means of quantitative in situ hybridization, employing gene-specific [35S]cRNA probes on rat brain cryostat sections. Regional analysis of the resulting changes in mRNA levels highlighted brain areas that belong in neuronal systems known to be especially sensitive to the action of ethanol. The results revealed systematically differential regulation for the three mRNA classes: the CaM I and CaM III mRNA levels displayed increases, and CaM II levels decreases in the affected brain regions, in both chronic ethanol- and withdrawal-treated animals. As regards the numbers of brain regions undergoing significant alterations in mRNA content, the CaM I mRNA levels exhibited changes in most brain areas, the CaM II levels did so in a lower number of brain regions, and the CaM III levels changed in only a few brain areas. These results suggest a differential regulation for the CaM genes in the rat brain and may help towards elucidation of the functional significance of the multiple CaM genes in the mammalian genome.
Brain Res Mol Brain Res 2000 Nov 10
PMID:Multiple calmodulin genes exhibit systematically differential responses to chronic ethanol treatment and withdrawal in several regions of the rat brain. 1107 96

Adaptive changes in gene expression are thought to contribute to dependence, addiction and other behavioral responses to chronic ethanol abuse. DNA array studies provide a nonbiased detection of networks of gene expression changes, allowing insight into functional consequences and mechanisms of such molecular responses. We used oligonucleotide arrays to study nearly 6000 genes in human SH-SY5Y neuroblastoma cells exposed to chronic ethanol. A set of 42 genes had consistently increased or decreased mRNA abundance after 3 days of ethanol treatment. Groups of genes related to norepinephrine production, glutathione metabolism, and protection against apoptosis were identified. Genes involved in catecholamine metabolism are of special interest because of the role of this pathway in mediating ethanol withdrawal symptoms (physical dependence). Ethanol treatment elevated dopamine beta-hydroxylase (DBH, EC 1.14.17.1) mRNA and protein levels and increased releasable norepinephrine in SH-SY5Y cultures. Acute ethanol also increased DBH mRNA levels in mouse adrenal gland, suggesting in vivo functional consequences for ethanol regulation of DBH. In SH-SY5Y cells, ethanol also decreased mRNA and secreted protein levels for monocyte chemotactic protein 1, an effect that could contribute to the protective role of moderate ethanol consumption in atherosclerotic vascular disease. Finally, we identified a subset of genes similarly regulated by both ethanol and dibutyryl-cAMP treatment in SH-SY5Y cells. This suggests that ethanol and cAMP signaling share mechanistic features in regulating a subset of ethanol-responsive genes. Our findings offer new insights regarding possible molecular mechanisms underlying behavioral responses or medical consequences of ethanol consumption and alcoholism.
Mol Pharmacol 2000 Dec
PMID:Expression profiling of neural cells reveals specific patterns of ethanol-responsive gene expression. 1109

The causes of non-trauma-mediated rhabdomyolysis are not well understood. It has been speculated that ethanol-associated rhabdomyolysis may be attributed to ethanol induction of skeletal muscle cytochrome P450(s), causing drugs such as acetaminophen or cocaine to be metabolized to myotoxic compounds. To examine this possibility, the hypothesis that feeding ethanol induces cytochrome P450 in skeletal muscle was tested. To this end, rats were fed an ethanol-containing diet and skeletal muscle tissue was assessed for induction of CYP2E1 and CYP1A1/2 by immunohistochemical procedures; liver was examined as a positive control tissue. Enzymatic assays and Western blot analyses were also performed on these tissues. In one feeding system, ethanol-containing diets induced CYP1A1/2 in soleus, plantaris, and diaphragm muscles, with immunohistochemical staining predominantly localized to capillaries surrounding myofibers. Antibodies to CYP2E1 did not react with skeletal muscle tissue from animals receiving a control or ethanol-containing diet. However, neither skeletal muscle CYP1A1/2 nor CYP2E1 was induced when ethanol diets were administered by a different feeding system. Ethanol consumption can induce some cytochrome P450 isoforms in skeletal muscle tissue; however, the mechanism of CYP induction is apparently complex and appears to involve factors in addition to ethanol, per se.
Exp Mol Pathol 2000 Dec
PMID:Ethanol-mediated CYP1A1/2 induction in rat skeletal muscle tissue. 1111 63

Ethanol and other drugs of abuse increase synaptic dopamine levels; however, little is known about how ethanol alters dopaminergic signaling. We have reported that ethanol induces translocation of delta and epsilon protein kinase C (PKC) in neural cells in culture. Using NG108-15 and Chinese hamster ovary cell lines that express the dopamine D2 receptor (D2R), we show here that the D2R agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide (NPA) also causes translocation of delta and epsilon PKC to the same sites as ethanol-induced translocation. D2R agonist and ethanol-induced translocation of delta and epsilon PKC share a common pathway that is blocked by pertussis toxin and requires phospholipase C (PLC) activity. These data suggest that both D2R agonists and ethanol activate PLC via a trimeric G protein leading to production of diacylglycerol with subsequent activation and translocation of delta and epsilon PKC. Moreover, ethanol and NPA, when present together at low concentrations that alone are ineffective, act synergistically to cause translocation of delta and epsilon PKC. Our data suggest that ethanol causes translocation of delta and epsilon PKC but cells expressing the D2R, such as neurons in the nucleus accumbens, may be particularly sensitive to low concentrations of ethanol.
Mol Pharmacol 2001 Jan
PMID:Ethanol acts synergistically with a D2 dopamine agonist to cause translocation of protein kinase C. 1112 36

Ethanol preference and behavioral disinhibition in AA (alcohol accepting) animals is a behavioral constellation similar to that seen in human type II alcoholism, for which considerable genetic loading has been shown. In search of novel neural substrates for this phenotype, we compared gene expression in the cerebral cortex of the AA rat with two groups of control animals, the ANA (alcohol non-accepting) line and heterogeneous Wistar animals, by differential display RT-PCR. We identified two transcripts, ribosomal protein L18a mRNA and diacyglycerol kinase iota mRNA, which are differentially expressed between AA and ANA rats. Ribosomal protein L18A mRNA is evenly expressed throughout the brain, but strongly reduced in cortex of AA rats vs controls. Diacylglycerol kinase iota is exclusively found in the brain, and expressed in a distinct regional pattern. Its cortical expression is about 25% higher in AA than ANA rats. Differential display RT-PCR seems to provide a feasible strategy to identify previously unknown genes whose differential expression correlates with behavioral phenotypes related to dependence.
Mol Psychiatry 2001 Jan
PMID:Differential expression of diacylglycerol kinase iota and L18A mRNAs in the brains of alcohol-preferring AA and alcohol-avoiding ANA rats. 1124 94

We have studied in vitro the effects of ethanol on the different enzymes involved in the biosynthesis of phosphatidylcholine (PC) via CDP-choline. Ethanol alters neither choline kinase (CK) nor CTP:phosphocholine cytidylyltransferase (CT) activities but, at levels higher than 50 mM, it does significantly inhibit microsomal cholinephosphotransferase (CPT) activity concomitantly with an increase in the ethanol concentration. A study of the kinetics of the reaction catalysed by CPT shows that ethanol decreases Vmax without altering Km, indicating a non-competitive inhibitory effect. An analysis of the thermodependence of CPT activity in the absence of ethanol reveals a break in the Arrhenius plot and thus a straight relationship between enzyme activity and the physico-chemical state of the microsomal membrane. Incubation of microsomes in the presence of ethanol increased the transition temperature from 25.8-28.2 degrees C. Microsomes were also incubated with n-alkanols with chain-lengths of fewer than five carbon atoms at concentrations which, according to their partition coefficients, produce equimolar levels in the membrane. Under these conditions all the alkanols caused the same inhibitory effect. All these results demonstrate that ethanol modulate the PC biosynthesis at the level of CPT activity and does not affect the CT enzyme. The inhibition found on CPT is clearly dependent on the alteration produced by ethanol on the hepatic microsomal membrane.
Mol Cell Biochem 2001 Jan
PMID:Modulation of biosynthesis of phosphatidylcholine via CDP-choline in rat liver: influence of ethanol on the microsomal cholinephosphotransferase activity. 1126 64

Prenatal ethanol exposure produces neural tube defects and growth retardation in experimental animals. Because ethanol's teratogenic effects may involve oxidative stress and effects may differ in vitro and in utero, glutathione, cysteine and ATP were evaluated in gestational day 10 rat conceptuses exposed to ethanol. Cultured embryos exposed to ethanol (1.5 or 3.0 mg/mL) maintained a concentration-dependent decrease in glutathione of 21 or 35%, respectively, at 6 h; visceral yolk sac (VYS) glutathione (GSH) decreased by 22 or 18%, respectively, at 3 h. Maternal ethanol exposure (4.5 g/kg) decreased glutathione by 30% in embryos and VYSs at 3 h, but values rebounded. Cultured embryonic cysteine decreased after 30 min by 42% with both doses and after 6 h by 32 or 38% with 1.5 or 3.0 mg/mL, respectively. Ethanol (1.5 mg/mL) increased VYS cysteine by 35% after 30 min. In utero ethanol exposure decreased embryonic cysteine by 58% at 3 h. Ethanol (1.5 mg/mL) decreased adenosine triphosphate (ATP) by 30-60% in embryos and VYSs at 30 min. After 6 h, embryonic ATP decreased by 41 and 30% with 1.5 and 3.0 mg/mL, respectively, while VYS ATP decreased by 38% with 1.5 mg/mL. In utero ethanol exposure decreased ATP by 31% at 3 h in VYSs. While decreases in GSH and cysteine were evident earlier in utero than in vitro, values returned to control suggesting embryos exposed in utero respond rapidly to chemical-induced oxidative stress due to maternal protective mechanisms. Differences between in vitro and in utero responses to ethanol have important implications for interpretation of in vitro developmental studies.
In Vitr Mol Toxicol 2000
PMID:Comparison of in vitro and in utero ethanol exposure on indices of oxidative stress. 1131 79

Alcohol is known to modulate the activity of a variety of neuroreceptors and ion channels. Recently, neuronal nicotinic acetylcholine receptors (nnAChRs) have become a specific focus of study because not only are they potently modulated by alcohol but also they regulate the release of various transmitters, including gamma-aminobutyric acid (GABA) and dopamine, which play an important role in the behavioral effects of ethanol. Whereas the potency of normal alcohols (n-alcohols) to potentiate GABA(A) receptors and to inhibit N-methyl-D-aspartate receptors increases with carbon chain length, we have found that n-alcohols, depending on the carbon chain length, exert a dual action, potentiation and inhibition, on nnAChRs in primary cultured rat cortical neurons. The mechanism of dual action of n-alcohols on nnAChRs was further analyzed using human embryonic kidney cells expressing the alpha 4 beta 2 subunits. Shorter chain alcohols from methanol to n-propanol potentiated acetylcholine (ACh)-induced currents, whereas longer chain alcohols from n-pentanol to n-dodecanol inhibited the currents. n-Butanol either potentiated or inhibited the currents depending on the concentrations of ACh and butanol. The parameters for both potentiation (log EC(200)) and inhibition (log IC(50)) were linearly related to carbon number, albeit with different slopes. The slope for potentiation was -0.299, indicating a change in free energy change (Delta Delta G) of 405 cal/mol/methylene group, whereas the slope for inhibition was -0.584, indicating a Delta Delta G of 792 cal/mol. These results suggest that potentiating and inhibitory actions are exerted through two different binding sites. Ethanol decreased the potency of n-octanol to inhibit ACh currents, possibly resulting from an allosteric mechanism.
Mol Pharmacol 2001 Oct
PMID:Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors. 1156 31

We have investigated the mechanisms by which acute ethanol inhibits the induction of long-term potentiation (LTP) in area CA1 of the rat hippocampal slice. In a previous report [Alcohol. Clin. Exp. Res. 21 (1997) 404] we demonstrated that ethanol produces only a modest inhibition of pharmacologically isolated N-methyl-D-aspartate receptors (NMDAR) in the CA1 region of the hippocampus. Moreover, this level of inhibition was not sufficient to account for ethanol's complete inhibition of LTP induction in this brain region. One possible explanation of these results is that we may have underestimated ethanol's ultimate effect on the NMDAR by focusing on pharmacologically isolated NMDAR responses. Ethanol might indirectly inhibit the NMDAR by, for example, potentiating the GABA(A)R. To explore this possibility, we first examined the effects of the GABA(A)R antagonist picrotoxin (PTX) and the allosteric GABA(A)R modulator flunitrazepam on NMDAR responses. We demonstrate that these modulators of GABA(A)R activity significantly affect the magnitude of synaptically evoked NMDAR responses. We next examined the effects of ethanol on NMDAR responses in the presence and absence of PTX. We see a significantly greater ethanol inhibition of the NMDAR when GABA(A)Rs are functional, i.e. in the absence of PTX. These data suggest that ethanol produces an inhibition of the NMDAR indirectly by affecting the GABA(A)R neurotransmission. Moreover, we found that ethanol inhibition of NMDAR activity, both directly through actions on the NMDAR, and indirectly, possibly through potentiation of GABA(A)R activity, is sufficient to account for ethanol's complete blockade of LTP induction.
Brain Res Mol Brain Res 2001 Oct 19
PMID:Evidence for a role for GABA(A) and NMDA receptors in ethanol inhibition of long-term potentiation. 1159 60


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