Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon superinduction, in the case of cell pretreatment with low doses of interferon (priming), may be explained by activation of 2',5'-oligoadenylate synthetase and endonuclease L, since the latter, as expected, leads to a more rapid amplification of the standard scheme of interferon induction based on the antirepression mechanism. In the given case, endonuclease L will further increase the degradation rates for messages, which encode repressor proteins controlling interferon gene expression. Under ordinary induction, these messages are destroyed only by short-lived nuclease activated by double-stranded RNA. Cell pretreatment with high doses of interferon (blocking) considerably increases the concentrations of protein kinase and 2',5'-oligoadenylate synthetase in the cell. However, it seems that during blocking protein kinase plays the main role in inhibition of interferon synthesis, and this leads to almost complete depression of translation in the cell. When protein kinase is not sufficiently activated, blocking does not occur since treatment of cells with high concentrations of interferon does not hinder priming induced by 2',5'-oligoadenylate synthetase and endonuclease L. The proposed model is consistent with the findings that both interferon-treated primed and blocked cells are able to produce interferon more rapidly than normal cells. The analysis, based on a computer simulation model, suggests that priming and blocking of interferon may be based on processes controlling its induction and antiviral activity.
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PMID:Theoretical analysis of the regulation of interferon expression during priming and blocking. 756 95

The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.
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PMID:Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase. 756 30

Freshwater turtles Trachemys scripta elegans endure prolonged severe hypoxia, and even complete anoxia, while diving or hibernating underwater. Metabolic adaptations supporting survival include the activation of glycogenolysis and glucose output from liver, as well as strong metabolic rate depression. The present study analyzes the enzymes of both the phosphorolytic (glycogen phosphorylase, phosphorylase b kinase, cAMP-dependent protein kinase) and glucosidic (alpha-glucosidase) pathways of glycogenolysis in turtle organs. Turtles were subjected to 5 hr of submergence in N2-bubbled water at 7 degrees C and then activities of phosphorolytic and glucosidic enzymes were assayed in liver, heart, brain, and red and white skeletal muscle, and compared with aerobic controls. In vitro incubations also assessed protein kinase A control of phosphorolytic enzymes. A functional enzyme cascade system for the activation of glycogen phosphorylase was found in all organs, and both phosphorylase and phosphorylase kinase were stimulated by in vitro incubation with the catalytic subunit of cAMP-dependent protein kinase. Anoxic submergence led to significant increases in phosphorylase activities in liver and heart (phosphorylase a rose 2- and 2.5-fold, respectively) but phosphorylase kinase and protein kinase A activities in liver were reduced after 5 hr exposure. Both acidic (pH 4) and neutral (pH 7) forms of alpha-glucosidase were detected in all five organs with highest activities in liver. Activity of acid alpha-glucosidase, which degrades lysosomal glycogen, increased by 2-fold in liver during anoxic submergence. The data show that glycogen breakdown in turtle liver during anoxic submergence may result from coordinated activations of both the cytoplasmic phosphorolytic and the lysosomal glucosidic pathways of glycogenolysis.
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PMID:Enzymatic control of glycogenolysis during anoxic submergence in the freshwater turtle Trachemys scripta. 758 17

Cerebellar long-term depression (LTD) is a model system of information storage in which a persistent attenuation of the parallel fiber-Purkinje neuron (PN) synapse is induced by conjunctive stimulation of parallel fiber and climbing fiber inputs at low frequency. As some studies have suggested that release of the gaseous second messenger, nitric oxide (NO), in the molecular layer and the consequent activation of soluble guanylate cyclase and cGMP-dependent protein kinase (PKG) in the PN, is necessary for LTD induction, we have further examined this hypothesis using a cell culture protocol. In cerebellar cultures made from transgenic mice in which the gene for neuronal nitric oxide synthase (nNOS) has been rendered null, LTD induced by glutamate/depolarization conjunctive stimulation was indistinguishable from that in cultures from wild-type mice in terms of amplitude, rate of onset, and duration. Bath application of cGMP analogs produced a large (80%), transient attenuation of glutamate-gated inward currents. However, application of an activator of soluble guanylate cyclase or an inhibitor of type V cGMP-phosphodiesterase did not mimic the effect of cGMP analogs, and inclusion of cGMP analogs in the patch pipette did not give rise to a slowly developing attenuation, suggesting that these compounds exert their effects at the cell surface. Free Ca was measured in the distal dendritic arbor of single PNs by fura-2 microfluorimetry.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An evaluation of the nitric oxide/cGMP/cGMP-dependent protein kinase cascade in the induction of cerebellar long-term depression in culture. 762 38

We suggest hypothetical mechanisms of posttetanic potentiation of inhibitory synaptic transmission (LTPi). Our previous results allow us to suppose that modifiable synapses are located on dendritic spines where metabotropic GABAb receptors (GABAbR) have been found. We assume that GABAbR may be involved in LTPi. Their activation leads to inactivation of protein kinases C and A (PKC and PKA) due to intracellular Ca++ decrease and inhibition of cAMP. This hypothesis is confirmed by the experiments in which LTP-like phenomena for early and late cortical IPSPs were shown to be the result of inactivation of PKA and PKC. We assume that metabolites of arachidonic acid 5- and 12-HPETE can be considered as retrograde messengers for LTPi. New hypothetical mechanisms underlying posttetanic homosynaptic long-term depression of excitatory synaptic transmission (LTDe) is also proposed. According to this hypothesis the target cell must be excited monosynaptically and inhibited disynaptically by the same tetanized afferents. LTDe may be induced only in those pathways which activate postsynaptic GABAb receptors. Both hypotheses are confirmed by experimental data and allow to explain some surprising experimental results.
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PMID:[The activation of GABA-B receptors, the decrease in intracellular Ca++ concentration and the inhibition of protein kinases--the possible mechanisms of prolonged posttetanic modification in the efficiency of inhibitory transmission in the neocortex]. 775 89

While there is considerable evidence that protein kinase activity is involved in memory formation, there has been, as yet, no direct investigation of a role for protein phosphatases. However, phosphatases have been implicated in the effects of the activation of glutamate receptors of the NMDA type, in long-term depression, and in the regulation of transmitter release and membrane ion channel activities, phenomena which have been shown to be possibly involved in cellular memorial processes. In the present paper, inhibition of protein phosphatase by 0.5 nM okadaic acid, a selective inhibitor of phosphatases 1 and 2A, is demonstrated to prevent memory consolidation in day-old chicks trained on a single trial passive avoidance task. Retention losses first occurred after 30 min post-learning, at an intermediate stage of memory formation preceding a protein synthesis-dependent long-term stage. It is suggested that protein phosphatase activity is involved in precursor processes to long-term memory consolidation.
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PMID:The impairment of long-term memory formation by the phosphatase inhibitor okadaic acid. 775 89

1. Whole-cell recordings were made from striatal neurones obtained from neonatal rats and maintained in primary cultures. The effects of dopamine D1 receptor activation were studied on the voltage-gated sodium current. 2. Bath application of a specific D1 agonist, SKF38393 (1 microM), reduced the neuronal excitability recorded in current-clamp by increasing the threshold for generation of action potentials. 3. In voltage-clamp recordings, SKF38393 (1 microM) reversibly reduced the peak amplitude of the sodium current by 37.8 +/- 4.95%. This effect was reversed by the D1 antagonist SCH23390 and was blocked by the intracellular loading of GDP-beta-S (2 mM) suggesting GTP-binding protein involvement. 4. The D1 agonist reduced the peak amplitude of the sodium current without significantly affecting (i) the voltage dependence of the current-voltage relationship, (ii) the voltage dependence of the steady-state activation and inactivation, (iii) the kinetics of the time-dependent inactivation, and (iv) the kinetics of recovery from inactivation. 5. The peak amplitude of the sodium current was progressively reduced by intracellular loading of cyclic AMP-dependent protein kinase (100 U ml-1). 6. Diffusion of a specific peptide inhibitor of the cyclic AMP-dependent protein kinase (PKI; 10 microM) into the cytosol of neurones blocked the effect of the D1 agonist on the sodium current amplitude. 7. These results demonstrate that dopamine acting at the D1 receptor reduces the amplitude of the sodium current without modifying its voltage- and time-dependent properties. This effect involves activation of the cyclic AMP-dependent protein kinase and results in a depression of the striatal neuronal excitability by increasing the threshold for generation of action potentials.
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PMID:Dopamine D1 receptor modulates the voltage-gated sodium current in rat striatal neurones through a protein kinase A. 777 43

1. Non-contractile Ca2+ mobilization (unaccompanied by muscle contraction) was initiated by nerve stimulation in the presence of neostigmine (more than 0.03 microM) at the endplate region of mouse diaphragm muscles. In the process of nicotinic receptor desensitization, the depressant effect of non-contractile Ca2+ on contractile Ca2+ mobilization was investigated by measurement of Ca(2+)-aequorin luminescence. 2. When the phrenic nerve was stimulated with paired pulses having intervals of 150, 300, 600, 1000 and 2000 ms, contractile Ca2+ transients were elicited during the generation of non-contractile Ca2+ mobilization. The amplitude of the contractile Ca2+ transients elicited by the second pulse (S2) was depressed at the shorter pulse intervals, but recovered to the initial contractile response (S1) at longer pulse intervals. 3. The extent of depression of S2 was enhanced by increasing the concentration of neostigmine (0.03 to 0.3 microM). When a low concentration (0.05 microM) of pancuronium, a competitive nicotinic antagonist, completely blocked non-contractile Ca2+ mobilization, the depression of S2 was diminished. 4. The depression of S2 was enhanced when the peak amplitude of non-contractile Ca2+ mobilization was raised by increasing the external Ca2+ concentration from 1.3 to 5 mM. 5. Staurosporine (10 nM), a protein kinase-C inhibitor, diminished the depression of S2 despite large amounts of non-contractile Ca2+ mobilization. The diminishing effect of staurosporine was counteracted by TPA (0.1 microM), a protein kinase-C activator. 6. These findings suggest that non-contractile Ca2+ mobilization may enhance the desensitization of the postsynaptic nicotinic receptor via activation of protein kinase-C at the neuromuscular junction.
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PMID:Postsynaptic nicotinic receptor desensitized by non-contractile Ca2+ mobilization via protein kinase-C activation at the mouse neuromuscular junction. 788 45

Isolated tissues from the land snail Otala lactea were used to examine the relationship between protein kinase activity and phosphorylation-induced changes associated with metabolic depression. Hepatopancreas and foot muscle were removed from active and estivating land snails and incubated in vitro under aerobic and anoxic conditions. Pyruvate kinase (PK), cAMP-dependent protein kinase (PKA), and protein kinase second messenger compounds (cyclic AMP and inositol 1,4,5-triphosphate) were measured after incubating the tissues for 4 hours. Pyruvate kinase from the hepatopancreas of active snails was phosphorylated during anoxic incubations as indicated by changes in the I50 value for L-alanine. However, measurements of PKA activity and of cellular cAMP concentrations suggested that PKA activity was lower in these incubated tissues. When foot muscle was used as the tissue source, incubation under anoxic conditions produced no changes in PK activity even though PKA activity was drastically reduced. Analysis of changes in inositol 1,4,5-triphosphate concentrations after tissue incubation showed that they were not consistent with changes in PK activity in either organ. These results suggest that PKA and Ca2+/phospholipid-dependent protein kinase C do not phosphorylate PK during anoxia in land snails. The differences between values measured in incubated tissues and those measured in vivo suggest that isolated O. lactea tissues are not a good in vitro model system for studying metabolic changes associated with depressed metabolism.
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PMID:Metabolic depression in land snails: in vitro analysis of protein kinase involvement in pyruvate kinase control in isolated Otala lactea tissues. 793 Nov 23

Both CA1 and dentate gyrus regions of the hippocampal slice exhibit an irreversible loss of synaptic transmission after exposure to in vitro ischemic conditions (buffer without oxygen and glucose). However, after shorter durations of ischemia (8-10 min) the CA1 region shows an irreversible loss of synaptic responses, whereas the dentate gyrus region completely recovers synaptic responses upon reoxygenation. To determine biochemical mechanisms underlying this differential susceptibility, we have examined changes in Ca2+/calmodulin-dependent protein kinase II (CaM-KII) and cyclic AMP-dependent protein kinase activities in homogenates from CA1 and dentate gyrus regions of the hippocampal slice after increasing durations of in vitro ischemia. Time-dependent changes in CaM-KII activities were correlated with changes in electrophysiological responses. CA1 homogenates from slices exposed to 1 min of ischemia showed significant increases in CaM-KII activity, whereas there was no significant change in kinase activity in dentate homogenates after 1 min of ischemia. However, after longer durations of ischemia (5, 10, and 20 min) we found a time-dependent reduction in CaM-KII activity in both CA1 and dentate gyrus regions, whereas no change was detected in cyclic AMP-dependent protein kinase activity. Irreversible depression of CaM-KII activity was seen at shorter durations of ischemia (10 min) in the CA1 region than in dentate region (20 min), which correlated with irreversible effects on synaptic responses. Immunoblot analysis showed that the decrease in CaM-KII activity was not due to degradation of CaM-KII protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activity of Ca2+/calmodulin-dependent protein kinase II following ischemia: a comparison between CA1 and dentate gyrus in a hippocampal slice model. 796 41


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