UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We performed experiments to examine the effects of an anti-fungal imidazole compound, econazole, on the regulation and effects of lipopolysaccharide-inducible nitric oxide synthase (iNOS) activity in rat aortic rings and cultured J774 murine macrophage cells. 2. In endothelium-intact rings of thoracic aorta, phenylephrine caused a concentration-dependent contraction with EC50 of 1.9 +/- 0.15 x 10(-8) M (n = 5). Following incubation with lipopolysaccharide (LPS, 5 micrograms ml-1) for 8 h there was a right-shift in the concentration-response curve (EC50 3.1 +/- 0.28 x 10(-7) M, P < 0.05) with a depression in the maximum contraction from 1.44 +/- 0.25 g to 0.86 +/- 0.26 g (n = 4). Co-incubation of rings with econazole (1 x 10(-5) M) partially inhibited the LPS-induced loss of reactivity to phenylephrine (EC50 6.5 +/- 0.72 x 10(-8) M) and fully inhibited the reduction in maximum tension (1.49 +/- 0.19 g; n = 5). 3. In J774 cells, incubation with LPS (10 micrograms ml-1, 24 h) resulted in significant nitrite production that was inhibited by co-incubation with econazole (IC50 5.0 +/- 0.9 x 10(-6) M; n = 5). In cells stimulated with LPS, production of L-[3H]-citrulline from L-[3H]-arginine was 6.41 +/- 0.22 pmol mg-1 protein min-1 (n = 3). This was inhibited by 92 +/- 6% by addition of NG-monomethyl-L-arginine (L-NMMA, 1 x 10(-3) M; n = 3) to the homogenate but not by econazole (1 x 10(-5) M; n = 3). In contrast pretreatment of cells with econazole (1 x 10(-5) M) markedly reduced the LPS-induced [3H]-citrulline production (0.86 +/- 0.053 pmol mg-1 protein min-1; P < 0.01; n = 3). 4. In cells treated with LPS and econazole, L-[3H]-citrulline production was restored in a concentration-dependent manner by addition of calmodulin (1 x 10(-8)-3 x 10(-7) M) with an IC50 of 4.2 +/- 0.9 x 10(-8) M. 5. We have shown that econazole inhibits the functional and biochemical activity of iNOS in rat aortic rings and cultured J774 cells. Treatment of cells with econazole renders the NO synthase functionally inactive. In econazole-treated cells enzyme activity is restored by calmodulin suggesting that econazole may inhibit the binding of this essential co-factor to the enzyme following its production. These studies may have implications for the design of novel anti-inflammatory agents working through the L-arginine-nitric oxide pathway.
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PMID:Functional effects of econazole on inducible nitric oxide synthase: production of a calmodulin-dependent enzyme. 888 96

A rise in Ca2+ concentration at postsynaptic sites provides an initial step in inducing both the long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. LTP induction requires the activation of Ca(2+)-sensitive protein kinases following the rise in Ca2+. By contrast, the activity of protein phosphatase(s) appears to be critical to induce LTD. Here we demonstrate that inhibition of the synthesis of calcineurin A alpha and A beta, catalytic subunits of Ca2+/calmodulin- (CaM) dependent protein phosphatase, reduces the threshold of induction for commissural-CA1 LTP in anesthetized rats. In rats administered antisense oligodeoxynucleotides (ODNs) against calcineurin A alpha and A beta intraventricularly for 7 days, a brief tetanic stimulation to the CA3 region, which in the control case was below threshold for the induction of LTP, now produced a long-lasting increase in both the EPSP slope and the amplitude of population spike recorded from the commissural-CA1 pathway. Western blot analysis of calcineurin showed that the threshold reduction was accompanied by a selective decrease in the protein levels in the hippocampus. Thus our study provides direct evidence that calcineurin per se has an antagonizing role in LTP induction. Complementary experiments with the selective calcineurin inhibitor, FK506, also showed the reduction of LTP threshold in a dose-dependent manner. These results, together with previous studies, support the hypothesis that the quantitative phosphorylation level of critical intracellular proteins determines whether the synaptic efficacy will increase or decrease after the activity-dependent rise in postsynaptic Ca2+.
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PMID:A facilitatory effect on the induction of long-term potentiation in vivo by chronic administration of antisense oligodeoxynucleotides against catalytic subunits of calcineurin. 888 51

We studied the effect of the adenylate cyclase activator forskolin, of protein kinase C-activating phorbol esters and of prolonged preganglionic input activation on the inhibitory response of the perfused superior cervical ganglion of the cat to exogenous met-enkephalin (Met-ENK). Met-ENK inhibited, in a concentration-dependent manner, the postganglionic compound action potential evoked by cervical sympathetic trunk stimulation. The inhibition was reversible, was blocked by naloxone as well as by pertussis toxin and showed no homologous desensitization in the concentration range 0.01-10 microM. Pretreatment of the ganglion with 4 beta-phorbol 12,13-dibutyrate or 4 beta-phorbol 12,13-diacetate depressed the Met-ENK response for several hours, while pretreatment with forskolin had no effect. This action of phorbol esters was prevented by the protein kinase inhibitor H-7 but not by the calmodulin antagonist W-7 or the protein kinase A inhibitor HA 1004 and was calcium-dependent. Recovery of the response from the depression produced by phorbol esters was not affected by a protein synthesis inhibitor. A 40 Hz 20 min stimulus train to the cervical sympathetic trunk mimicked the effect of phorbol esters, depressing for several hours the inhibition produced by Met-ENK. Stimulus trains of duration shorter than 5 min or frequency lower than 5 Hz were ineffective. This effect of prolonged preganglionic stimulation occurred even when the stimulus train was delivered during complete block of nicotinic and muscarinic ganglionic transmission but was lost when the stimulus train was delivered during perfusion with calcium-free Krebs. The protein kinase inhibitor H-7 prevented the depression of the Met-ENK response by the train, while W-7 and HA 1004 had no effect. These findings suggest that, in the superior cervical ganglion of the cat, a kinase, activated by phorbol esters and inhibited by H-7, exerts a long-term control of the ganglion cell responsiveness to opiate receptor activation. A similar mechanism can be synaptically activated by a non-cholinergic transmitter, released by the preganglionic axons during prolonged, high frequency, activity.
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PMID:Long-term depression of a sympathetic ganglionic response to opioids by prolonged synaptic activity and by phorbol esters. 896 46

The regulatory myosin light chain (MLC) is phosphorylated in cardiac muscle by Ca2+/calmodulin-dependent MLC kinase (MLCK) and is considered to play a modulatory role in the activation of myofibrillar adenosine triphosphatase (ATPase) and the process of force generation. Since the depression in cardiac contractile function in chronic diabetes is associated with a decrease in myofibrillar ATPase activity, we investigated changes in MLC phosphorylation in diabetic heart. Rats were made diabetic by injecting streptozotocin (65 mg/kg intravenously), and the hearts were removed 8 weeks later; some 6-week diabetic animals were injected with insulin (3 U/d) for 2 weeks. Changes in the relative MLC and MLCK protein contents were measured by electrophoresis and immunoblot assay, whereas phosphorylated and unphosphorylated MLCs were separated on 10% acrylamide/urea gel and identified by Western blot. MLC and MLCK contents were decreased markedly (40% to 45%) and MLC phosphorylation was decreased significantly (30% to 45%) in the diabetic rat heart homogenate in comparison to control values. The changes in MLC and MLCK content in diabetic heart were partially reversible, whereas changes in MLC phosphorylation were normalized upon treatment with insulin. These results suggest that decreased protein contents of MLC and MLCK and phosphorylation of MLC may contribute to the depression of cardiac myofibriliar ATPase activity and heart dysfunction in diabetic cardiomyopathy.
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PMID:Myosin light-chain phosphorylation in diabetic cardiomyopathy in rats. 900 73

Postischemic delayed neuronal death is attributed to excitotoxic activation of glutamate receptors. It is preceded by a persistent inhibition of protein synthesis, the molecular basis of which is not known. Here we have examined in cortical neurons in culture the regulation by glutamate of phosphorylation of eukaryotic elongation factor-2 (eEF-2) by eEF-2 kinase, a Ca2+/calmodulin-dependent enzyme. Using a phosphorylation state-specific antibody, we show that glutamate, which triggers a large influx of Ca2+, enhances dramatically the phosphorylation of eEF-2. On the basis of kinetic and pharmacological analysis, we demonstrate a close correlation among the increase in cytosolic Ca2+ concentration, the degree of eEF-2 phosphorylation, and the inhibition of protein synthesis. A 30 min treatment with NMDA induced a transient phosphorylation of eEF-2 and delayed neuronal death. However, pharmacological inhibition of protein translation was not neurotoxic by itself and protected neurons against the toxicity evoked by low concentrations of NMDA. Thus, phosphorylation of eEF-2 and the resulting depression of protein translation may have protective effects against excitotoxicity and open new perspectives for understanding long-term effects of glutamate.
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PMID:Glutamate-dependent phosphorylation of elongation factor-2 and inhibition of protein synthesis in neurons. 913 70

Single-residue mutations have been made of the hydrophobic Ile or Val residue in position 8 of each of the four calcium-binding loop sequences (sites I-IV) of Drosophila calmodulin. These highly conserved residues are part of the hydrophobic core of either calmodulin domain and are involved in the structural link of two calcium-binding sites via a short antiparallel beta-sheet. In the apo-form, the replacement of Ile (or Val) by Gly causes a significant destabilization, shown by the unfolding of the secondary structure of the domain carrying the mutation. In the presence of calcium, the deficiency in alpha-helical structure at 20 degrees C is restored for the mutants at site I, II, or III but not at site IV, which requires the further binding of a high-affinity target peptide to re-establish the native conformation. The extent of the destabilization is seen in the depression of the melting temperature of individual domains, which can be as large as 80 degrees C in the case of Ca4-CaM(V136G). However, because of low values of the unfolding enthalpy for calmodulin domains, only relatively low values of <2 kcal/mol are implied for DeltaDeltaG, the free energy of destabilization due to mutation. Consistent with this, the secondary structure of any unfolded mutant domain is highly sensitive to solvent composition and is largely refolded in the presence of 12.5% (v/v) aqueous trifluoroethanol. Compared to wild-type calmodulin, the affinities of the mutants for calcium and target peptides from sk-MLCK at 20 degrees C are significantly reduced but the effects are relatively small. These results indicate that the conformation of calmodulin can be dramatically altered by mutation of a single highly conserved residue but that changes in solvent or the binding of a target sequence can readily compensate for this, restoring the wild-type properties. The results also suggest that the integrity of both the apo- and holo-forms of calmodulin is important for the maintenance of its biological function and confirm the importance of conserving the structural function of the residues involved in the beta-sheet interactions.
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PMID:The role of beta-sheet interactions in domain stability, folding, and target recognition reactions of calmodulin. 923 1

In this review, we attempt to cover the descriptive, biochemical and molecular biological work that has contributed to our current knowledge about RC3/neurogranin function and its role in dendritic spine development, long-term potentiation, long-term depression, learning, and memory. Based on the data reviewed here, we propose that RC3, GAP-43, and the small cerebellum-enriched peptide, PEP-19, belong to a protein family that we have named the calpacitins. Membership in this family is based on sequence homology and, we believe, a common biochemical function. We propose a model wherein RC3 and GAP-43 regulate calmodulin availability in dendritic spines and axons, respectively, and calmodulin regulates their ability to amplify the mobilization of Ca2+ in response to metabotropic glutamate receptor stimulation. PEP-19 may serve a similar function in the cerebellum, although biochemical characterization of this molecule has lagged behind that of RC3 and GAP-43. We suggest that these molecules release CaM rapidly in response to large influxes of Ca2+ and slowly in response to small increases. This nonlinear response is analogous to the behavior of a capacitor, hence the name calpacitin. Since CaM regulates the ability of RC3 to amplify the effects of metabotropic glutamate receptor agonists, this activity must, necessarily, exhibit nonlinear kinetics as well. The capacitance of the system is regulated by phosphorylation by protein kinase C, which abrogates interactions between calmodulin and RC3 or GAP-43. We further propose that the ratio of phosphorylated to unphosphorylated RC3 determines the sliding LTP/LTD threshold in concept with Ca2+/ calmodulin-dependent kinase II. Finally, we suggest that the close association between RC3 and a subset of mitochondria serves to couple energy production with the synthetic events that accompany dendritic spine development and remodeling.
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PMID:RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes. 939 8

The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics. The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca2+-independent activity of Ca2+- and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDA-dependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation.
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PMID:Hippocampal synaptic plasticity in mice overexpressing an embryonic subunit of the NMDA receptor. 959 97

The metabotropic receptor mGluR6 is localized to the dendrites of On bipolar cells and mediates synaptic input from photoreceptors. The binding of glutamate to the receptor activates a phosphodiesterase (PDE), which then hydrolyzes cGMP. A nonselective cationic conductance, believed to be gated directly by cGMP, is turned off as a result of the fall in cGMP levels, and the cell hyperpolarizes. Here we present evidence for regulation of the conductance by an additional mechanism that it is independent of cGMP. Whole-cell recordings were obtained from On bipolar cells in slices of tiger salamander retina. Dialysis of cells with 1 microM KN-62 or 10 microM KN-93, two inhibitors of type II calmodulin-dependent protein kinase (CaMKII), depressed cGMP-dependent currents. This depression persisted when hydrolysis of cGMP was prevented with IBMX, a broad-spectrum PDE inhibitor, suggesting that CaMKII acts downstream from the PDE in the cascade. The depression of cGMP-dependent currents was probably not due to a direct interaction of the inhibitors with the channels as neither 1 microM KN-62 or 10 microM KN-93 was found to have any effect on cyclic nucleotide-gated channels when applied directly to excised patches of rod outer segments. We propose that phosphorylation by CaMKII may be an important mechanism for regulating the cGMP-dependent conductance of On bipolar cells.
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PMID:Regulation of cGMP-dependent current in On bipolar cells by calcium/calmodulin-dependent kinase. 960 27

Much evidence points to a significant involvement of the classical neurotransmitters 5-HT and DA in affective disorders with possible changes in different structures of the CNS and also at different levels of the signal transduction chain, i.e., receptor, synthesis, uptake or release. We have used chronic isolated housing as an animal model of depression. These isolated rats enabled the study of KCl-induced release of 5-HT and DA from nucleus accumbens, prefrontal cortex and hippocampal slices. The following questions were addressed: first, if there is a change in the depolarization dependent release of DA and 5-HT from these CNS structures, and second, if the release is through the classical exocytotic mechanism. A significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when compared to controls. 5-HT release was completely abolished from controls or isolated animals, when slices were incubated with Krebs containing zero Ca2+/10 mM Mg2+, the inorganic Ca2+ channel blockers, Cd2+ or Ni2+ and the calmodulin inhibitor, trifluoperazine. The organic Ca2+ channel blockers nifedipine and D-600 were less effective in inhibiting the stimulated 5-HT release. KCl stimulated DA release was only significantly increased from hippocampus slices, of isolated, but not control animals. This release was also highly Ca2+-dependent. The basal release of DA and 5-HT was similar in control and isolated animals and was not affected by the Ca2+ channel antagonists. The results suggest that extracellular Ca2+-dependent release of 5-HT and, to a lesser degree, of DA, is increased in this chronic animal model of depression in several CNS structures.
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PMID:Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats. 978 82

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