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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ADP-induced aggregation of human platelets is markedly increased after preincubation with lithium chloride, whereas lithium has the opposite effect on rabbit platelets. Since this phenomenon might be related to cAMP metabolism, the influence of lithium on total cAMP content and adenylate cyclase activity was investigated. Lithium does not significantly change the total cAMP content of human platelets neither during incubation nor during ADP-induced aggregation. Basal adenylate cyclase activity, however, was slightly inhibited by lithium in human platelets. The inhibition of adenylate cyclase by ADP appeared to be enhanced by lithium. Prostacyclin induced stimulation of adenylate cyclase is counteracted by this ion. In rabbit platelets the prostacyclin stimulated adenylate cyclase activity is not affected by lithium. These data suggest that a correlation exists between the influence of lithium on the aggregation of human and rabbit platelets and the sensitivity of their adenylate cyclase for this ion.
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PMID:Lithium inhibits adenylate cyclase of human platelets. 626 68

In a previous study 11 depressed patients were treated with salbutamol, a beta-2 adrenergic agonist, and beta-2 adrenergic receptor sensitivity was evaluated by measuring the plasma cyclic AMP rise after an iv dose of salbutamol. Salbutamol treatment induced subsensitivity of the beta-adrenergic adenylate cyclase with a time course paralleling the antidepressant effects. In the present study nine patients who were depressed despite treatment with lithium were treated with salbutamol plus lithium. Subsensitivity of the beta-adrenergic adenylate cyclase developed in the presence of lithium to the same degree as in patients treated with salbutamol alone. These results represent the first human study of the theory that lithium stabilizes receptor sensitivity changes. Lithium's failure to prevent subsensitivity agrees with reports that lithium fails to prevent impramine-induced subsensitivity of beta-adrenergic receptors in rat cortex. Lithium stabilization of receptor sensitivity of beta-adrenergic receptors in rat cortex. Lithium stabilization of receptor sensitivity would therefore appear to be unidirectional, preventing supersensitivity but not subsensitivity.
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PMID:Lithium does not prevent agonist-induced subsensitivity of human adenylate cyclase. 628 46

Lithium is a unique drug in its clinical profile in psychiatry. Lithium has numerous biochemical effects, but none has yet been proven to be its mode of therapeutic action. Inhibition of noradrenaline-sensitive adenylate cyclase is reviewed as the only biochemical effect of lithium shown to occur in both animals and man at therapeutic lithium concentrations. A tetracycline antibiotic, demeclocycline, also blocks noradrenaline-sensitive adenylate cyclase. A clinical trial of demeclocycline in mania would provide a test of the adenylate cyclase theory of lithium action.
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PMID:Clinical implications of research on the mechanism of action of lithium. 631 Jun 96

A suggested cause of mania is asynchrony of two biologic clocks that are involved with the sleep-waking mechanism. Increased norepinephrine in the synaptic clefts of the locus ceruleus could quicken the pace of one clock. That same increase in norepinephrine is a possible inducer of euphoria and hyperactivity in mania. The action of melatonin and/or vasotocin on the dorsal raphe nucleus may induce the hallucinatory behavior in mania. Lithium corrects the psychosis by inhibiting adenylate cyclase and slowing the circadian rhythm.
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PMID:A mechanism of mania and the chemistry of dreams: a hypothesis. 639 Jun 94

Rats were treated with lithium, imipramine, reserpine, and lithium combined with imipramine or reserpine. Lithium was given in the diet (40 mmol/kg) resulting in a serum-Li+ level of 0.5-0.6 mmol/l. Other drugs were dissolved in 0.9% saline and given intraperitoneally once or twice daily. After 3 weeks of treatment, forskolin-stimulated adenylate cyclase activity was measured in cerebral cortex homogenates. Reserpine did not affect the forskolin stimulation, while both imipramine and lithium caused a decrease in this activity. The combined treatments lithium-imipramine and lithium-reserpine also exhibited a clear decrease in forskolin stimulation, but the effect of concomitant lithium and imipramine treatment did not differ from the effect seen after any of the treatments alone. The unstimulated activity was unaltered by all treatments. The inhibition of lithium and imipramine on the forskolin stimulation indicates an interference of these two drugs with the forskolin-mediated activation of the adenylate cyclase.
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PMID:Forskolin-stimulated adenylate cyclase activity in rat cerebral cortex following chronic treatment with psychotropic drugs. 654 99

The sliding-tubule hypothesis of flagellar movement has strong experimental support, but our present knowledge of the mechanism by which this sliding is coordinated and converted into flagellar oscillation and bend propagation is quite limited. Among the few facts known are: (1) calcium has a role in regulating the asymmetry of flagellar waveform, (2) the initiation or activation of motility in spermatozoa from several species involves a cyclic AMP-dependent phosphorylation reaction, and (3) the conversion of tubule sliding to bending does not require the radial spokes or central tubules. Inhibitors are valuable tools for investigating mechanisms involved in cellular function, and we report here that Li+ in low concentrations reversibly inhibits the microtubule-based movement of reactivated sea urchin sperm flagella. The evidence indicates that the action of Li+ is directed primarily towards one or more regulatory sites through which Ca2+ modulates the asymmetry of flagellar waveform, rather than towards dynein ATPase itself. Lithium also appears to inhibit the sperm adenylate cyclase, but this action does not seem to be relevant to its inhibition of normal motility. Our findings indicate the need for considerable caution when using ATP analogues supplied as the Li+ salt.
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PMID:Lithium reversibly inhibits microtubule-based motility in sperm flagella. 672 11

A consensus AP-1 site in the promoter of the rat neurotensin/neuromedin N (NT/N) gene is a critical regulatory element required for synergistic regulation by combinations of nerve growth factor (NGF), lithium, glucocorticoids, and adenylate cyclase activators. A rapid RNase protection assay was developed to examine the kinetics of NT/N gene activation and to determine whether activation requires newly synthesized proteins. Either NGF or lithium in combination with dexamethasone and forskolin transiently activated NT/N gene expression, but with distinct kinetics. Protein synthesis was not required for activation when NGF was used as the permissive inducer, but was required for the rapid down-regulation of the response. In contrast, lithium responses were attenuated in the absence of protein synthesis, consistent with a requirement for newly synthesized AP-1 complexes in activation. In all cases, increases in NT/N gene expression closely paralleled increases in AP-1 binding activity. Lithium in combination with other inducers caused delayed increases in both AP-1 binding activity and c-jun, c-fos and fra-1 gene expression. These results indicate that NGF and lithium exert their effects on NT/N gene expression through distinct pathways. The lithium pathway is active in neuronally-differentiated PC12 cells and could potentially be involved in the regulation of NT/N gene expression in the nervous system.
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PMID:Synergistic induction of neurotensin gene transcription in PC12 cells parallels changes in AP-1 activity. 789 6

Lithium is thought to have an insulin-like effect on glucose transport and metabolism in skeletal muscle and adipocytes. However, we found that lithium had only a minimal effect on basal glucose transport activity in rat epitrochlearis muscles. Instead, lithium markedly increased the sensitivity of glucose transport to insulin, so that the increase in glucose transport activity induced by 300 pM insulin was approximately 2.5-fold greater in the presence of lithium than in its absence. Lithium also caused a modest increase in insulin responsiveness. This enhancement of the susceptibility of the glucose transport process to stimulation was not limited to insulin, because lithium induced increases in the susceptibility of glucose transport to stimulation by contractile activity, hypoxia, a phorbol ester, and phospholipase C. Lithium also blunted the activation of glycogen phosphorylase by epinephrine. These effects were not mediated by inhibition of adenylate cyclase, because neither basal- nor epinephrine-stimulated muscle cAMP concentration was affected by lithium treatment. The effects of lithium on glucose transport and metabolism in skeletal muscle are strikingly similar to the persistent effects of exercise. These results support the possibility that lithium might be useful in the treatment of insulin resistance in patients with non-insulin-dependent diabetes mellitus.
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PMID:Lithium increases susceptibility of muscle glucose transport to stimulation by various agents. 801 55

It has been estimated that in most industrialized countries 1 person out of every 1000 in the population is undergoing lithium treatment to stabilize their episodic mood disturbances due to manic-depressive illness. Lithium may stabilize mood swings by altering the action of certain neurotransmitters at the synaptic level in the brain. Recent research suggests that lithium alters neurotransmission by affecting neurotransmitter-coupled second messenger systems. A major second messenger system is the adenylate cyclase, which generates intracellular cAMP from ATP. The adenylate cyclases (type I-IV) are regulated by stimulatory and inhibitory receptors, which either stimulate or inhibit the adenylate cyclase activity. The stimulatory and inhibitory neurotransmitter-receptor signals are transferred to the catalytic unit of the adenylate cyclase by Gs and Gi, respectively. The activated receptor induces GTP stimulation of the heterotrimeric G protein, leading to a dissociation of the protein into the active alpha*GTP and the beta gamma complex. The former stimulates the catalytic unit of adenylate cyclase. The stimulation is terminated by a GTPase located on the alpha subunit that converts GTP to inactive GDP. At present, G proteins are known to play a central role in coupling receptors to effector proteins. In addition to extracellular regulation due to neurotransmitters, some adenylate cyclases (type I, III) are regulated by CaM as a consequence of enhanced intracellular concentrations of free Ca2+. The Ca(2+)-dependent stimulation of adenylate cyclase by CaM is assumed to occur by a direct effect on the catalytic unit. The catalytic units sensitive to Ca(2+)-CaM are also subjected to regulation by stimulatory and inhibitory neurotransmitter stimuli. Magnesium is essential for adenylate cyclase activity, since MgATP2- is the enzyme substrate. Furthermore, one Mg2+ site located on the G protein regulates both the receptor agonist affinity and the dissociation of the G protein during the activation cycle. A second Mg2+ site on the catalytic unit is responsible for Mg2+ regulation of the catalytic activity. The present work aimed at investigating the mechanisms by which lithium in vitro and after chronic treatment (ex vivo) affects adenylate cyclase activities in various regions of the rat brain. Lithium in vitro and ex vivo inhibited the selective stimulation of adenylate cyclase by Ca(2+)-CaM in the cerebral cortex. Furthermore, lithium in vitro interacted directly with the catalytic unit of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actions of lithium on the cyclic AMP signalling system in various regions of the brain--possible relations to its psychotropic actions. A study on the adenylate cyclase in rat cerebral cortex, corpus striatum and hippocampus. 814 86

Forskolin is a diterpene derivative that activates adenylate cyclase and raises cAMP levels in the cell. Both i.p. and i.c.v. forskolin cause behavioral hypoactivity. Lithium has been reported for many years to block cAMP accumulation, but the behavioral relevance of this biochemical effect is not clear. We studied the effect of acute and chronic lithium on icv forskolin-induced hypoactivity. Acute lithium had no effect, but chronic lithium significantly blocked forskolin-induced hypoactivity. The effect of chronic lithium occurred with both forskolin in DMSO and with a water-soluble forskolin derivative. These results suggest that this behavioral model can be used to investigate whether new inhibitors of adenylate cyclase possess lithium-like effects.
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PMID:The effect of acute and chronic lithium on forskolin-induced reduction of rat activity. 945 26


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