Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lithium is an effective drug for both treatment and prophylaxis of bipolar disorder. However, the mechanism of lithium action is still unknown. The inositol depletion hypothesis is supported by biochemical and behavioral data in rats, but primate inositol levels are higher than in rodents and may obviate the effects of depletion. Inhibition of 5HT autoreceptors by lithium is supported by biochemical and behavioral data in rats but would seem more related to lithium's antidepressant than to its antimanic or prophylactic effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2. This effect could be most relevant for treatment of neurodegenerative disorders. Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range of signal transduction pathways. However, this lithium effect occurs at high concentrations and may be more relevant for its toxic effect. Lithium in low concentrations induces accumulation of PAP, which affects several cellular processes including RNA processing. However, PAP phosphatase is present more in peripheral tissues than in brain. This lithium effect could explain some of its peripheral side effects. Chronic lithium administration upregulates glutamate reuptake and thus decreases glutamate availability in synapse. Glutamate is an excitatory neurotransmitter and its reduction could exert an antimanic effect. Biochemical and clinical experiments are necessary to determine the key mechanism of lithium efficacy in treatment and prophylaxis of affective disorders.
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PMID:The mechanism of lithium action: state of the art, ten years later. 1138 81

Lithium inhibits glycogen synthase kinase-3 (GSK-3), which leads to an increase of cytoplasmic beta-catenin levels. In some cell types, but not in others, activated beta-catenin interacts with members of the lymphoid enhancer-binding factor (LEF)/T-cell factor (TCF) family of transcription factors and induces gene expression. Lithium effect on LEF/TCF-mediated gene expression has never been evaluated in cells with a neuronal phenotype. We have constructed a LEF/TCF-dependent luciferase reporter gene to investigate lithium effects on transcription in PC12 cells. In transiently transfected PC12 cells, lithium induced a time-dependent increase in LEF/TCF-mediated luciferase activity. These results are consistent with the known inhibitory effects of lithium on GSK-3 and represent the first demonstration that a LEF/TCF responsive element also mediates lithium-induced gene expression in PC12 cells.
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PMID:Lithium induces gene expression through lymphoid enhancer-binding factor/T-cell factor responsive element in rat PC12 cells. 1175 Sep 94

Lithium inhibits (Li(+)) glycogen synthase kinase-3 (GSK-3) by competition for magnesium (Mg(2+)), but not ATP or substrate. Here, we show that the group II metal ion beryllium (Be(2+)) is a potent inhibitor of GSK-3 and competes for both Mg(2+) and ATP. Be(2+) also inhibits the related protein kinase cdc2 at similar potency, but not MAP kinase 2. To compare the actions of Li(+) and Be(2+) on GSK-3, we have devised a novel dual inhibition analysis. When Be(2+) and ADP are present together each interferes with the action of the other, indicating that both agents inhibit GSK-3 at the ATP binding site. In contrast, Li(+) exerts no interference with ADP inhibition or vice versa. We find, however, that Li(+) and Be(2+) do interfere with each other. These results suggest that Be(2+) competes for two distinct Mg(2+) binding sites: one is Li(+)-sensitive and the other, which is Li(+)-insensitive, binds the Mg:ATP complex.
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PMID:Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites. 1179 68

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.
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PMID:A common mechanism of action for three mood-stabilizing drugs. 1201 4

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 x 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.
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PMID:Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. 1251 38

Lithium is highly effective in the treatment of bipolar disorders and has multiple effects on embryonic development, glycogen synthesis, hematopoiesis and other biological processes. However, the mechanism of lithium action is still unclear. A variety of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of second messenger, and the protein kinase glycogen synthase kinase-3. This article proposes that multiple actions of lithium are critical for its therapeutic effects, and that these complex effects stabilize neuronal activities, support neural plasticity and provide neuroprotection.
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PMID:[Mechanism of action of lithium: intracellular signaling pathways]. 1269 Apr 9

Manic-depression, or bipolar affective disorder, is a prevalent mental disorder with a global impact. Mood stabilizers have acute and long-term effects and at a minimum are prophylactic for manic or depressive poles without detriment to the other. Lithium has significant effects on mania and depression, but may be augmented or substituted by some antiepileptic drugs. The biochemical basis for mood stabilizer therapies or the molecular origins of bipolar disorder is unknown. One approach to this problem is to seek a common target of all mood stabilizers. Lithium directly inhibits two evolutionarily conserved signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. A number of GSK-3 substrates are involved in neuronal function and organization, and therefore present plausible targets for therapy. Valproic acid (VPA) is an antiepileptic drug with mood-stabilizing properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene expression through inhibition of histone deacetylase. These effects, however, are not conserved between different cell types. VPA also inhibits inositol signaling through an inositol-depletion mechanism. There is no evidence for GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol-depletion mechanism as seen with lithium and VPA. Studies on the enzyme prolyl oligopeptidase and the sodium myo-inositol transporter support an inositol-depletion mechanism for mood stabilizer action. Despite these intriguing observations, it remains unclear how changes in inositol signaling underlie the origins of bipolar disorder.
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PMID:Search for a common mechanism of mood stabilizers. 1282 61

Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.
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PMID:Neurodevelopment and mood stabilizers. 1294

Bipolar disorder is increasingly recognized as an illness that may progress to impairment in neurocognitive functioning and cell loss in cortical and limbic brain regions. Glutamatergic damage and/or damage due to high glucocorticoid levels that inhibit adult neurogenesis are likely contributing mechanisms. Drug treatments with possible neuroprotective effects are becoming increasingly important both clinically and as research tools. Mood stabilizing drugs and lithium in particular may act to prevent neuronal damage and tissue loss that may occur in the brain of patients with bipolar disorders. Lithium has been shown to exert neuroprotective effects in vitro and to stimulate neurogenesis in the hippocampus. Animal studies have demonstrated pharmacological effects of lithium suggestive of its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of signal transduction intermediates such as myo-inositol, protein kinase C, phosphotidylinositol-3 kinase (PI-3K)/protein kinase B (Akt), ras-mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3alpha and -3beta and calcium. It remains to be established whether lithium treatment protects against possible cell damage in the same manner as it protects against recurrences of the illness. We propose to examine the effect of long-term lithium treatment on neurocognitive functioning of bipolar patients and the use of lithium in the treatment of chronic neuropsychiatric disorders.
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PMID:Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. 1467 87

Anterograde organelle transport is known to be inhibited by overexpression of the microtubule-associated protein tau in cultured cells. However, the molecular mechanism regulating this function of tau protein has not previously been understood. We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3beta and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. This phosphorylation did not alter tau's ability to bind to microtubules but appeared to be required for the maintenance of the anterograde organelle transport in differentiated cells. Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. In CHO cells transfected with human tau(441), mitochondrial clustering was found in cells in which tau was unphosphorylated. These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport.
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PMID:Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. 1507 27


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