Mg2+ - ATPase

Nonsteroidal SERMs can also amplify signal-induced Ca2+ surges by inhibiting Ca2+-calmodulin-dependent membrane (Ca2+ + Mg2+)-ATPase. For instance, in synaptic plasma membranes and red cell membrane ghosts, tamoxifen and other triphenylethylene compounds (but not estradiol) have been... 

Malva JO, Lopes MCF, Vale MGP, Carvalho AP (1990) Actions of antiestrogens on the (Ca2+ + Mg2+)-ATPase and Na+/Ca2 + exchange of brain cortex membranes. Biochem Pharmacol 40 1877-1884... 

Mitochondrial oligomycin-sensitive mg2+ATPase is thought to play a major role in oxidative phosphorylation (Boyer et al. 1977). It has been suggested that impairment of mitochondrial energy metabolism by chlordecone may contribute to the decreases in body weight observed following exposure to this chemical (Desaiah 1981). 

Desaiah D, Ho IK, Mehendale HM. 1977a. Effects of Kepone and mirex on mitochondrial Mg2+-ATPase in rat liver. Toxicol Appl Pharmacol 39 219-228. 

O. T. Jones, R. J. Froud, and A. G. Lee, Interactions of hexachlorocyclohexanes with the (Ca2t+Mg2)-ATPase from sarcoplasmic reticulum, Biochim. Biophys. Acta 812, 740-751 (1985). 

The inhibition of membrane Ca2+/Mg2+ ATPase leads to a derangement of Ca2+ levels, which will damage the mitochondria and hence also indirectly contribute to ATP depletion. Inhibition of y-glutamyl cysteine synthetase reduces the ability of the liver cell to synthesize new GSH, so reducing its ability to protect itself. Overall, some 17 enzymes have been shown to be inhibited ex vivo after treatment of animals and another 14 are known to have bound paracetamol and may or may not be inhibited. 

The best studied example of a Group IIA cation transport system is the calcium pump of the sarcoplasmic reticulum of skeletal muscle. Indeed, the calcium pump and the sodium pump represent the most studied of all transport processes. The calcium pump involves a membrane-bound (Ca2+, Mg2+)-ATPase and uptake of Ca2+ is associated with hydrolysis of ATP. While the... 

Various aspects of the (Ca2+, Mg2+)-ATPase have been reviewed.126 133 It can be isolated in vesicular form from homogenized skeletal muscle. Since it is the major protein component of SR membranes, it can also be isolated fairly easily in relatively pure form. The enzyme has a molecular weight in the range 100 000-120 000, and forms oligomers in the SR membranes, probably tetramers.133 Each subunit is associated with about 30 molecules of phospholipid, which are suggested to form a shell or annulus around the protein. The monomeric subunit has ATPase activity, and remains monomeric throughout the enzyme cycle,136 although the behaviour of the monomer is dependent on the solubilization procedure. 37... 

Trypsin hydrolysis of SR vesicles cleaves the (Ca2, Mg2+)-ATPase into three fragments, NH2-20 000, 30 000 and 45 OOO-COOH. The phosphorylation site is associated with an aspartic acid residue in the 30 000 fragment and ionophoric activity with the 20 000 fragment. The amino terminus of the enzyme is located on the cytoplasmic side of the membrane.143... 

Most mechanisms for the (Ca2+, Mg2+)-ATPase are modifications of the proposal of deMeis et a/.128 An example is shown in Figure 9. The ATPase can utilize CaATP and MgATP as substrates.147 Two moles of Ca2+ are bound per mole of the phosphorylation site with high affinity, followed by phosphorylation of the enzyme by ATP. Conformational changes in the phosphoprotein lead to the calcium sites being accessible to the intravesicular space, with decrease in their affinity for... 

A variety of other calcium transport systems are associated with Ca21-activated ATPases. The extraembryonic structure, the chorioallantoic membrane, of the chick embryo is responsible for the translocation of over 120 mg of eggshell calcium into (he embryo during development. The enzyme responsible for this is a (Ca2+, Mg2+)-ATPase with Km values for Ca2+ of 30 p,mol dm-3 and 0.3 mmol dm-3, and a molecular weight of 170 000. The enzyme can be crossiinked and co-isolated with a calcium-binding protein.158 Transport of Ca2+ is also associated with (Ca2+, Mg2+)-ATPases in neutrophil plasma membranes,159 transverse tubule membranes from rabbit skeletal muscle,160 rabbit myocardial membrane,161 endoplasmic reticulum,162 sar-colemma,163 brain microsomes,164 the Golgi apparatus165 and rat liver plasma membranes.166... 

Gould GW, Colyer J, East JM, et al. 1987. Silver ions trigger Ca2+ release by interaction with the (Ca2+-Mg2+) -ATPase. J Biol Chem 262 7676-7679. 

Mas-Oliva, J., Perez-Montfort, R., Cardenas-Garcia, M. and Rivas-Duro, M., 1991, Altered coupling states between calcium transport and (Ca2+, Mg2+)-ATPase in the AS-30D ascites hepatocarcinoma plasma membrane. Mol Cell Biochem 100, 39—50. 

Ion transport is central to nerve impulse transmission both along the axon and at the synapse and many neurotoxicants elicit effects by interfering with the normal transport of these ions (Figure 11.6). The action potential of an axon is maintained by the high concentration of sodium on the outside of the cell as compared to the low concentration inside. Active transporters of sodium (Na+K+ ATPases) that actively transport sodium out of the cell establish this action potential. One action of the insecticide DDT resulting in its acute toxicity is the inhibition of these Na+K+ ATPases resulting in the inability of the nerve to establish an action potential. Pyrethroid insecticides also elicit neurotoxicity through this mechanism. DDT also inhibits Ca2+Mg2+ ATPases, which are important to neuronal repolarization and the cessation of impulse transmission across synapses. 

It is not yet clear which estimates of the ratio between the levels of protein and of carbohydrate metabolism during hypoxia should be regarded as reliable. It seems likely that the increase in respiratory quotient in freshwater fish to values of 2.5-2.8, as found by Mohamed and Kutty (1983a, 1986), indicates a predominance of protein expenditure over that of carbohydrate. A hypoxic environment shifts the acid-base balance of the fish towards acidosis (Kotsar, 1976), thereby inducing the redistribution of electrolytes, alteration of ion exchange and the activity of Na+-K+-Mg2+-ATPases and alkaline phosphatases. It also leads to an increased level of C02 in the blood, which enhances the bicarbonate buffer system (Kotsar, 1976). In section 2.1, we... 

Other intermediate-duration oral studies in rats evaluated effects of aluminum on brain chemistry as well as neurobehavioral performance. Rats that consumed 51 mg Al/kg/day as aluminum chloride in drinking water for 180 days had alterations in behavior (reduced spontaneous locomotor activity, impaired learning, extinction and relearning of an active avoidance task, impaired maze relearning ability) and brain chemistry (increased lipid peroxidation, decreased activity of Na+-, K+-, and Mg2+-ATPases) (Lai et al. 1993). Ingestion of 490 mg Al/kg/day as aluminum sulfate in drinking water for 4-12 weeks caused reduced retention of a learned passive avoidance task and changes in brain chemistry (e.g., increased cyclic adenosine monophosphate levels, decreased concentrations of MAP-2 and other structural... 

Mn2+ binding studies of the type described above with purified kidney (Na+ + K+)-ATPase (21) and Mg2+-ATPase (23) have yielded biphasic Scatchard plots in each case (Figure 1). 

Figure IB. Scatchard plot of the binding of Mn2 to Mg2 -ATPase from sheep kidney medulla (23). The free Mn2 was determined by EPR. The solid curves were fitted to the data by computer.

Mata, A.M., Matthews, I., Tunwell, R.E.A., Sharma, R.P., Lee, A.G., East, J.M. (1992). Definition of surface-exposed and trans-membranous regions of the (Ca2+-Mg2+)-ATPase of sarcoplasmic reticulum using anti-peptide antibodies. Biochem. J. 286, 567-580. 

---