Brain Na+, K+-ATPase: Alteration of Ligand Affinities and Conformation by Chronic Ethanol and Noradrenergic Stimulation In Vivo (original) (raw)
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Effects of short-chain alcohols and norepinephrine on brain (Na+, K+)ATPase activity
Biochemical Pharmacology, 1986
ATPase activity in synaptic membranes from whole brains of mice was inhibited by a series of short-chain aliphatic alcohols (ethanol through pentanol). The relationship of inhibitory potency to alcohol chain length and to alcohol membrhne : water partition coefficient suggested that the inhibitory effect of the alcohols does not depend totally on their interaction with neuronal membrane lipids. Although partitioning into the membranes is important for this inhibitory effect, a direct interaction of alcohol with the enzyme protein may also be involved in the inhibition. Norepinephrine did not significantly potentiate inhibition of (Na รท,K+)ATPase activity by low concentrations of ethanol in preparations of either mouse or rat brain. Thus, under our conditions, ethanol, at levels which can be reached in vivo, only slightly inhibited enzyme activity, and the possible importance of this inhibition in mediating the in vivo acute or chronic effects of ethanol on the CNS remains open to question.
Pharmacology Biochemistry and Behavior, 1980
An alcohol dependent states was induced in rats via gastric intubation. Alcohol was given three times daily for seven days in increasing doses, the final dose and concentration varying from rat to rat, being adjusted according to weight loss and state of intoxication. After seven days dosing, alcohol was withdrawn and twenty hours later an audiogenic stimulus was given to induce convulsions. Na+K+ATPase activity was measured in the hippocampus of rats during alcohol administration and during withdrawal. Animals which received twenty-one doses of alcohol showed a significant increase in Na+K+ATPase activity compared with controls. On withdrawal of alcohol, the enzyme activity fell, but remained higher than control values. In the withdrawal groups, membrane Na+K+ATPase levels were increased significantly compared to control levels in the order: no convulsion less than with convulsion less than postconvulsion. It is concluded that Na+K+ATPase activity is modified during chronic alcohol administration and during seizures induced after alcohol withdrawal by audiogenic stimulation.
Effects of ethanol on ouabain inhibition of mouse brain (Na+,K+)ATPase activity
Biochemical Pharmacology, 1987
Plots of ouabain inhibition of mouse cerebral cortical (Na+,K+)ATPase activity fitted a twosite model significantly better than a one-site model, consistent with the presence of two forms of the enzyme with different affinities for ouabain. The fraction of enzyme activity with high affinity for ouabain (HAO: Ki = 500 nM), suggested to be localized neuronally, constituted the major portion (60-70%) of activity. Ouabain inhibition of both components of enzyme activity was reduced as KC1 concentrations were increased. In vitro, only high concentrations of ethanol affected (Na+,K+)ATPase activity and ouabain inhibition of activity. Ethanol (500 mM) selectively reduced the activity, and increased the sensitivity to ouabain inhibition, of the HA0 component, with no significant effect on the low-affinity (LAO) component. On the other hand, following chronic treatment of mice with ethanol in vivo, in a paradigm that produced tolerance and physical dependence, the sensitivity to ouabain of the HA0 form of the enzyme was selectively increased. The relative proportions, and the activities of the HA0 and LAO components, were not altered. The effects of ethanol, added in vitro, on the HA0 component
Ethanol's Effects on Cortical Adenylate Cyclase Activity
Journal of Neurochemistry, 1985
The effects of ethanol o n P-adrenergic receptor-coupled adenylate cyclase (AC) of mouse cerebral cortex were examined. The addition of ethanol (20-500 mM) to incubation mixtures containing cortical membranes demonstrated that ethanol could increase AC activity and potentiate the stimulatory effects of guanylylimidodiphosphate [Gpp(NH)p] on AC activity. Ethanol increased the rate of activation of AC by guanine nucleotides and concomitantly decreased the EC,, for magnesium required to achieve maximal stimulation of cortical AC. The EC,, values for Gpp(NH)p and isoproterenol stimulation of AC activity were also altered by ethanol. Ethanol was capable of stimulating AC extracted by use of digitonin. The AC activity in the digitonin extract was no longer sensitive to the addition of Gpp(NH)p or NaF, but was still stimulated by ethanol. We propose multiple sites of action for ethanol in stimulating cortical AC activity. These sites include actions at the P-adrenergic receptor, at the GIF coupling proteins, and at the catalytic unit of cortical AC. Comparison of ethanol's actions on cortical p receptor coupled AC activity with prior reported actions of ethanol on striatal dopamine (DA)-sensitive AC indicated differential sensitivities of these two AC systems to ethanol. These differences may be determined by specific coupling characteristics of the striatal and cortical AC systems or by differences in the plasma membranes in which striatal and cortical AC systems are located.
Journal of Neurochemistry, 1987
Chronic ingestion of ethanol, which produced tolerance and physical dependence, resulted in altered function of the cerebral cortical 0-adrenergic receptor-coupled adenylate cyclase system in mice. Although there was no change in basal adenylate cyclase activity, or in the activity of the digitonin-solubilized catalytic unit, stimulation of adenylate cyclase activity by the nonhydrolyzable guanine nucleotide analog guanylylimidodiphosphate [Gpp(NH)pJ was reduced in brains of ethanol-fed animals. Ethanol added in vitro increased adenylate cyclase activity, and this enhancement, in the presence of Gpp(NH)p, was also reduced in cortical membranes of ethanol-fed mice. Furthermore, the maximal response to isoproterenol was decreased, and the ECJo for isoproterenol stimulation of adenylate cy-clase activity was increased in ethanol-fed animals. The results are consistent with a qualitative or quantitative defect in the function of the stimulatory guanine nucleotide-binding protein (N,), as well as in the P-adrenergic receptor, after chronic ethanol exposure. In part, these changes appear to be similar to those that occur during heterologous desensitization of various receptor systems, and may be associated with dependence on or tolerance to ethanol.
The Journal of Biological Chemistry, 1983
W e examined effects of ethanol and dimethyl sulfoxide on the regulation and apparent thermodynamic properties of moderate affinity Na+ and K+ binding that regulates the K+-dependent phosphatase activity of (Na+,K+)-ATPase. Ethanol and other alcohols reduced the apparent affinity for Na' and K+ at their moderate affinity sites and increased the negative AH and A S of cation binding. Dimethyl sulfoxide had the opposite effects. Inhibition by ethanol was favored by high temperature or low K+. Ethanol potentiated inhibition of K+ binding by ATP or Mg2+. Ethanol also shifted the equilibrium between K+-sensitive and -insensitive forms of (Na+,K+)-ATPase toward the K+sensitive form; in this case, it reduced the negative AH and A S for the transition to K+-sensitive enzyme. Again, dimethyl sulfoxide had the opposite effects. These data indicate that ethanol and other agents considered to affect membrane fluidity act by a combination of membrane (on cation binding) and solvent (on conformation) effects. The most important effect of ethanol and similar agents on the enzyme is to prevent the formation of K+-sensitive enzyme by cation binding and to destabilize K+-sensitive enzyme in the presence of ATP. These results also add further evidence that the sites by which Na+ and K+ produce K+-sensitive enzyme are similar or identical.
Differential effects of ethanol on the striatal and cortical adenylate cyclase system
The Japanese Journal of Pharmacology, 1987
In the present study, effects of ethanol (EtOH) on C57/BL mouse cortical l9-adrenergic receptor coupled adenylate cyclase (AC) were shown to be different from the effects of EtOH on striatal dopaminergic-stimulated AC activity. The addition of EtOH (500 mM) increased the AC activity by 60% in cortical mem brane and by less than 10% in striatal membrane preparations in the absence of