Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large series of CNS active drugs have been tested for their possible effect on the Mg+2 dependent ATPase associated with isolated synaptic vesicles. Antipsychotic agents and cocaine showed inhibition, of a non-competitive type. The implications of this finding for a synaptic theory of psychosis are discussed.
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PMID:Interaction of psychoactive drugs with the Mg+2 requiring ATPase associated with isolated synaptic vesicles. 24 Nov

Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
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PMID:Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms. 129 67

The effects of chronic manganese (Mn) treatments (1 and 10 mg MnCl2.4H2O per ml of drinking water) from conception onwards on brain regional development of sodium-potassium-activated and magnesium-activated adenosine triphosphatases (Na-K-ATPase and Mg-ATPase) were studied. The activities of these enzymes were determined in hypothalamus, cerebellum, pons and medulla, striatum, midbrain and cerebral cortex (which included the hippocampus) of Mn-treated and age-matched control rats at 5 postnatal ages. Both ATPase activities doubled in most brain regions between day 5 and day 20 postnatal. In pons and medulla, striatum, midbrain, and cerebral cortex, adult levels of both enzymatic activities were attained by day 20 postnatal. Na-K-ATPase activities transiently increased in the midbrain (+25%) at day 12 with the lower Mn dose and in the cerebral cortex (+31%) at day 20 with the higher Mn dose. With the higher Mn dose only, Mg-ATPase activities were increased in the hypothalamus (+20%) at day 12 and in the pons and medulla (+22%) at day 20 but were decreased in the pons and medulla (-20%) at day 60. Thus, only transient changes in enzymatic activities were observed despite dose-dependent increases in the brain levels of Mn resulting from the Mn treatment. A hypothesis regarding the role of early but transient changes in brain metabolism in the pathogenesis of the initial psychotic symptoms in Mn intoxication was proposed and discussed in relation to several other observations of a similar nature.
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PMID:Effects of chronic manganese treatment on rat brain regional sodium-potassium-activated and magnesium-activated adenosine triphosphatase activities during development. 166 39

Serum tryptophan and erythrocyte Na+/K+ ATPase were determined in 14 epileptics with and without psychosis. The nature of the psychosis in four patients was non-specific. The amino acid and the enzyme levels were also estimated in 11 patients with a diagnosis of functional affective psychosis, 14 patients with schizophrenia, and 9 normal subjects. Comparison of data among the patients and the normal subjects were done using analysis of variance. There were no significant differences in tryptophan profiles and Na+/K+ ATPase levels in epileptics with or without psychosis. In addition, the data obtained for these parameters for the schizophrenics were homogenous to those of epileptics. Significant differences were, however, obtained between the epileptics and patients with affective illness. The data thus suggested that the non-specific psychosis presented by the epileptics may be schizophrenia-like and lend support to a specific psychosis associated with epilepsy.
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PMID:Blood tryptophan and ATPase in psychosis of epilepsy. 182 59

An hypothesis is presented to explain and integrate experimental and clinical observations on manic-depressive (bipolar or biphasic) psychosis. The model is based on alterations in the activity of the sodium, potassium-activated adenosine triphosphatase (Na, K-ATPase) pump. A reduction in the activity of the Na,K-ATPase can be responsible for both phases of the disorder.
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PMID:The Na,K-ATPase hypothesis for manic-depression. I. General considerations. 632 18

Patients suffering from manic-depressive psychosis, manic type (ICD 296.0), were treated with lithium carbonate and randomly allocated to two groups, one received digoxin and the other matching placebo for 7 days. Severity of mania was rated by psychiatrists on the Manic Rating Scale and Analogue Line on days 0 and 7 and by nurses daily on the Hargreaves Rating Scale, Psychotic Rating. Fourteen patients received digoxin and lithium carbonate and 14 patients received placebo and lithium carbonate. Improvement in the placebo lithium group was significantly greater than that in the digoxin lithium group. This trial suggests, therefore, that the effect of inhibition of membrane cation carrier is to reduce the response to lithium. This result is in keeping with our hypothesis that an increase in Na-K ATPase is essential to the therapeutic effect of lithium carbonate. It does not, however, exclude the possibility that the observations resulted from the inhibition by digoxin of lithium entry into the brain.
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PMID:The effect of digoxin on the response to lithium therapy in mania. 680

Previous studies have shown decreased erythrocyte membrane (EM) Na,K-ATPase activity in chronic patients suffering from schizophrenia (SCH). There are no data about changes at the onset of psychosis and enzyme kinetics. Increased lipid peroxidation could be responsible for alterations in Na,K-ATPase activity. Substrate kinetics pattern of EM Na,K-ATPase and levels of lipid peroxides in plasma and erythrocytes were measured in (1) patients with first episode of psychosis (n=20) before medication and after the first 3 weeks of treatment, (2) chronic medicated schizophrenic patients (n=52) in the exacerbation phase, and (3) age- and sex-matched control subjects (n=30). All patients were assigned to groups with predominantly positive or predominantly negative symptoms on the basis of their scores on Positive and Negative Syndrome Scale (PANSS). In first-episode patients with predominantly negative symptoms before treatment, uncompetitive inhibition of Na,K-ATPase was noticed. The first-episode patients with predominantly positive symptoms had increased enzyme catalytic activity. After 3 weeks of treatment, activities were normalized in both groups. Among chronic patients, uncompetitive inhibition was found only in patients with predominantly negative symptoms. Plasma lipid peroxides (thiobarbituric acid-reactive substances [TBARS]) were elevated in both groups of patients with first episode of psychosis. Despite the presence of peroxidative injury indicative for the loss of membrane phospholipid essential fatty acids, the activities of Na,K-ATPase differ between SCH (+) and SCH (-) patients.
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PMID:Substrate kinetics of erythrocyte membrane Na,K-ATPase and lipid peroxides in schizophrenia. 1269 78

The fluorinated anti-psychotic drug trifluoperazine (TFP) has been shown to be a K(+)-competitive inhibitor of gastric H(+)/K(+)-ATPase, a membrane-embedded therapeutic target for peptic ulcer disease. This paper describes how variable contact time (19)F cross-polarization magic angle spinning (VCT-CP/MAS) NMR has been used to probe the inhibitory interactions between TFP and H(+)/K(+)-ATPase in native gastric membranes. The (19)F CP/MAS spectra for TFP in H(+)/K(+)-ATPase enriched (GI) gastric membranes and in control membranes containing less than 5 nmol of the protein indicated that the drug associates with the membranes independently of the presence of H(+)/K(+)-ATPase. The (19)F peak intensities in the VCT-CP/MAS experiment confirmed that TFP undergoes slow dissociation (k(off) < 100 s(-1)) from binding sites in GI membranes, and more rapid dissociation (k(off) < 100 s(-1)) from control membranes. The spectra showed that up to 40% of bound TFP was displaced from GI membranes by 100 mM K(+) and by the K(+)-competitive inhibitor TMPIP, but TFP was not displaced from the control membranes. Hence the spectra of TFP in GI membranes represent the drug bound to the K(+)-competitive inhibitory site of H(+)/K(+)-ATPase and to other non-specific sites. The affinity of TFP for the K(+)-competitive site (K(D) = 4 mM) was determined from a binding curve of (19)F peak intensity versus TFP concentration after correction for non-specific binding. The K(D) was much higher than the IC(50) for ATPase inhibition (8 microM), which suggests that the substantial non-specific binding of TFP to the membranes contributes to ATPase inhibition. This novel approach to probing ligand binding can be applied to a wide range of membrane-embedded pharmaceutical targets, such as G-protein coupled receptors and ion channels, regardless of the size of the protein or strength of binding.
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PMID:Insights into the interactions between a drug and a membrane protein target by fluorine cross-polarization magic angle spinning NMR. 1474 1

The mode of action of the cation lithium is not well known. It is at present used as a topical drug in dermatology. Lithium inhibits many enzymes: Na/K ATPase, adenylcyclase, enzymes of the prostaglandines E1 synthesis, inositol-1-phosphatase. It is active on neutrophils et T lymphocytes, explaining in part its anti-inflammatory activity. It has a dose-dependent action on levures. It has possibly a direct inhibitory activity on DNA synthesis of herpes viruses. Lithium has a good local safety. Percutaneous penetration is weak and plasma concentrations are very much lower than that observed after oral intake. Lithium has been studied in seborrhoeic dermatitis. Its efficacy was primarily observed in psychotic patients. An assay with oral lithium did not confirmed the first observations. Topical lithium was found more efficient. Topical lithium succinate associated with zinc sulfate and lithium gluconate had a greater efficacy than placebo. Comparison with topical ketoconazole showed a non inferiority of lithium gluconate. Oral lithium also showed a reduction of symptoms' duration of herpes simplex. Cutaneous side-effects of oral lithium are frequent and numerous. Some of them may be explained by a lithium pharmacological cell activity (such as psoriasis). Teratogenicity is observed in mice and rats. Drug interactions are not expected after topical application. Irritants side effects are mainly observed after topical application; they are moderate and transitory. Lithium gluconate treatment of seborrhoeic dermatitis is a bid application during at least 8 weeks. It may be used in renal insufficiency. It is not recommended in the first trimester of pregnancy.
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PMID:[Lithium]. 1510 43

Wilson's disease is an infrequent, autosomic recessive pathology, resulting from a loss of function of an adenosine triphosphatase (ATP7B or WDNP), secondarily to a change (more than 60 are described currently), insertion or deletion of the ATP7B gene located on the chromosome 13q14.3-q21.1, which involves a reduction or an absence of the transport of copper in the bile and its accumulation in the body, notably the brain. Wilson's disease is transmitted by an autosomic recessive gene located on the long arm of chromosome 13. The prevalence of the heterozygote is evaluated at 1/90 and the homozygote at 1/30,000. Consanguinity, frequent in the socially geographically isolated populations, increases the prevalence of the disease. The toxic quantities of copper, which accumulate in the liver since early childhood and perhaps before, remain concentrated in the body for years. Hence, cytological and histological modifications can be detected in the biopsies, before the appearance of clinical or biological symptoms of hepatic damage. The accumulation of copper in the liver is due to a defect in the biliary excretion of metal and is accompanied invariably by a deficit in ceruloplasmin; protein synthesized from a transferred ATP7B gene, which causes retention of the copper ions in the liver. The detectable cellular anomalies are of two types: hepatic lesions resulting in acute hepatic insufficiency, acute hepatitis and finally advanced cirrhosis and lesions of the central nervous system responsible for the neurological and psychiatric disorders. In approximately 40-50% of the patients, the first manifestation of Wilson's disease affects the central nervous system. Although copper diffuses in the liver towards the blood and then towards other tissues, it has disastrous consequences only in the brain. It can therefore cause either a progressive neurological disease, or psychiatric disorders. Wilson's disease begins in the form of a hepatic, neurological, or psychiatric disease in at least 90% of the patients. In some rare cases, the first manifestations of the disease can be psychiatric which, according to the literature, accounts for only 10% of the cases. The disease can be revealed by isolated behavioral problems, an irrational syndrome, a schizophrenic syndrome, or a manic-depressive syndrome. Damage to the central nervous system can be more severe, thus, several differential diagnoses have been discussed: a psychotic disorder of late appearance; a depressive state; a mental confusion disorder. The clinical syndrome is complex. Indeed, it is the polymorphism, which dominates in the description of the psychiatric demonstrations of the disease. This can lead to prejudicial diagnostic wandering, particularly since heavy sedative treatment may be required to suppress behavioral problems. Clinically, Wilson's disease generally appears between the age of 10 and 20. It rarely remains masked until after the age of 40. The first manifestations are hepatic (40% of the cases), neurological (35%) or psychiatric (10%). The inaugural disorder can finally take on a haematological, renal, or mixed form in approximately 15% of the cases. We have detailed the principal clinical elements. In approximately 40-50% of the patients, the first manifestation of the disease affects the central nervous system, where it can cause either a progressive neurological disease, or psychiatric disorders. The ophthalmologic disorder is dominated by Kayser-Fleischer's ring, representing a green or bronze colored ring on the periphery of the cornea. It occupies the higher pole of the cornea, then the lower pole, and extends to the whole circumference. It is generally only visible under examination with a slit lamp. It disappears on average within 3-5 years following copper chelating therapy. Kayser-Fleischer's ring has been described other than in Wilson's disease, in exceptional cases of prolonged cholestasis. On haematological level, the hyperhaemolysis is due to the toxicity of the ionic copper, released massively in the plasma by hepatocellular necrosis. The other manifestations can be found in the following organs: renal, osteoarticular, cardiac, endocrine, cutaneous, and in the teguments. Until 1952, the diagnosis was evoked only on clinical symptomatology. It can henceforth be marked unambiguous, even in the absence of any symptom, by the description of a ceruloplasmin plasma concentration of less than 200 ml/l, and of a Kayser-Fleischer's ring. Hepatic copper on sample is constantly increased during the disease (from 3 to 25 micromol/g of dry weight). On the other hand, the absence of a reduction in the plasma ceruloplasmin does not make it possible to exclude the diagnosis. Conversely, a reduction in ceruloplasmin can exist other than in Wilson's disease (nephritic syndrome, malabsorption syndrome, or severe hepatic insufficiency). Kayser-Fleischer's ring is quasiconstant among patients with neuropsychiatric demonstrations (thus, its absence represents a very strong argument against the diagnosis). It can on the other hand be lacking during hepatic forms, and in this case, its absence is not an argument against the diagnosis. Magnetic resonance imaging can reveal abnormal signals of the grey cores. A genetic study is conducted by liaison analysis in the event of a family history of the disease. When it is not treated, Wilson's disease induces lesions of the tissues, the outcome of which is always fatal. Treatment relies on the regulation of copper chelation, which improves the prognosis, and zinc, which captures the copper in a nontoxic form. The severe psychiatric disorders observed during Wilson's disease may require tranquilizers, but care should be taken because of potential neurological or hepatic side effects. Lithium seems an interesting treatment and remains theoretically indicated, taking into account the scarcity of the extrapyramidal symptoms and the hepatic dysfunction among patients at the stage of cirrhosis, since it is not metabolized in the liver. Although rare, it is important to approach Wilson's disease in psychiatry because the psychiatric manifestations can precede the somatic disorders and help to pose the diagnosis. We stress the importance of the early diagnosis of the pathology, the outcome of which is fatal in the absence of specific treatment.
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PMID:[The onset of psychiatric disorders and Wilson's disease]. 1878 84


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