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

In cerebellar long-term depression (LTD), conjunctive stimulation of parallel and climbing fiber inputs to a Purkinje neuron (PN) results in a selective depression of parallel fiber-PN synaptic strength. A similar phenomenon may be induced in the cultured PN when glutamate pulses and PN depolarization, which mimic the effects of parallel and climbing fibers, respectively, are coapplied. Here, we show that LTD can be induced in two very reduced preparations of the postsynaptic neuron; an acutely dissociated preparation and a perforated outside-out macropatch of dendritic membrane. LTD in these preparations retains properties of that seen in an intact cultured PN in that it is not induced by either glutamate pulses or depolarization alone and requires calcium influx, mGluR activation, and PKC activation for induction. As both of these preparations lack dendritic spine compartments, these findings suggest that the associative nature of LTD induction does not require this level of morphological organization.
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PMID:Defining a minimal computational unit for cerebellar long-term depression. 878 Jun 56

A hypothetical mechanism is proposed for the induction of long-term posttetanic potentiation of the efficiency of inhibitory synaptic transmission (LTPi). The data we have previously obtained have made it possible to hypothesize that modifiable inhibitory synapses are situated on the dendritic spines on which there are metabotropic GABAb receptors. It is hypothesized that modification of inhibitory transmission is determined precisely by these receptors, the activation of which leads to inactivation of protein kinases C and A (PKC and PKA) as a result of a decrease in the intracellular concentration of Ca++ and the inhibition of cAMP. The hypothesis is confirmed by experiments in which it was demonstrated that an effect similar to LTPi took place as a result of the inactivation of PKC and PKA. It is hypothesized that eicanoid [sic] acids may be retrograde messengers during LTPi. A new hypothetical mechanism underlying long-term depression of excitatory transmission (LTDe) is proposed, according to which tetanized afferent fibers must simultaneously monosynaptically excite and disynaptically inhibit one and the same postsynaptic cell. LTDe may be induced only in those pathways which activate [are activated by--unclear from Russian text--Trans.] GABAb receptors. The proposed hypothesis make it possible to explain the results of certain experiments.
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PMID:Activation by GABAb, reduction of the intracellular concentration of Ca++, and inhibition of protein kinases are possible mechanisms of the long-term posttetanic modification of the efficiency of inhibitory transmission in the new cortex. 880 74

Animal survival during severe hypoxia and/or anoxia is enhanced by a variety of biochemical adaptations including adaptations of fermentative pathways of energy production and, most importantly, the ability to sharply reduce metabolic rate by 5-20 fold and enter a hypometabolic state. The biochemical regulation of metabolic arrest is proving to have common molecular principles that extend across phylogenetic lines and that are conserved in different types of arrested states (not only anaerobiosis but also estivation, hibernation, etc.). Our new studies with anoxia-tolerant vertebrates have identified a variety of regulatory mechanisms involved in both metabolic rate depression and in the aerobic recovery process using as models the freshwater turtle Trachemys scripta elegans and garter snakes Thamnophis sirtalis parietalis. Mechanisms include: 1) post-translational modification of cellular and functional proteins by reversible phosphorylation and changes in protein kinase (PKA, PKC) and/or phosphatase activities to regulate this, 2) reversible enzyme binding associations with subcellular structural elements, 3) differential gene expression and/or mRNA translation producing new mRNA variants and new protein products, 4) changes in protease activity, particularly the multicatalytic proteinase complex, and 5) both constitutive and anoxia-induced modifications to cellular antioxidant systems to deal with oxidative stress during the anoxic-aerobic transition of recovery.
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PMID:Metabolic adaptations supporting anoxia tolerance in reptiles: recent advances. 893 40

Protein kinase C was purified to homogeneity from liver of the anoxia-tolerant turtle (Trachemys scripta elegans). Two isozymes were present and were identified as PKC alpha and PKC beta by hydroxylapatite chromatography and cross-reaction with specific antibodies to the mammalian isozymes. Kinetic characterization of the isozymes showed that both required phospholipids and Ca2+ for activation and both were inhibited by low concentrations of PKC inhibitors. The PKC alpha was activated more strongly by phosphatidylinositol and lysophosphatidylinositol compared with PKC beta. Treatment with trypsin did not activate turtle PKC isozymes, but generated inactive PKC beta, whereas PKC alpha was resistant to inactivation. Anoxia exposure of turtles in vivo, via submergence in N2-gassed water at 7 degrees C, altered the activity and subcellular distribution of PKC in liver. After 1 hr of anoxic exposure at 7 degrees C, the activity of membrane-bound PKC had increased by 2.4-fold and represented a translocation of 40% of PKC beta and more than 80% of PKC alpha from the cytosol to the membrane-associated fraction. With longer submergence, however, membrane-bound PKC activity was suppressed again. This two-phase response to anoxia by PKC suggests that an activation of PKC, through its translocation to the membrane, is important in mediating the initial metabolic responses to submergence, which include an activation of glycogenolysis during the hypoxia transition period. With sustained anoxia exposure, the subsequent reduction of PKC activity may be part of the overall mechanism of metabolic rate depression that allows endurance of prolonged anoxia.
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PMID:Liver protein kinase C isozymes: properties and enzyme role in a vertebrate facultative anaerobe. 902 85

1. Long-term potentiation and its counterpart long-term depression are two forms of activity dependent synaptic plasticity, in which protein kinases and protein phosphatases are essential. 2. B-50/GAP-43 and RC3/neurogranin are two defined neuronal PKC substrates with different synaptic localization. B-50/GAP-43 is a presynaptic protein and RC3/neurogranin is only found at the postsynaptic site. Measuring their phosphorylation state in hippocampal slices, allows us to simultaneously monitor changes in pre- and postsynaptic PKC mediated phosphorylation. 3. Induction of LTP in the CA1 field of the hippocampus is accompanied with an increase in the in situ phosphorylation of both B-50/GAP-43 and RC3/neurogranin, during narrow, partially overlapping, time windows. 4. Pharmacological data show that mGluR stimulation results in an increase in the in situ phosphorylation of B-50/GAP-43 and RC3/neurogranin.
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PMID:Protein kinase C in synaptic plasticity: changes in the in situ phosphorylation state of identified pre- and postsynaptic substrates. 915 64

Using patch-clamp techniques we studied several aspects of intracellular GABA(A) and glycine Cl- current regulation in cortical and spinal cord neurons, respectively. Activation of PKA with a permeable analog of cyclic AMP (cAMP) produced a potentiation of the Cl- current activated with glycine, but not of the current induced with GABA. The inactive analog was without effect. Activation of PKC with 1 microM PMA reduced the amplitude of the GABA(A) and glycine currents. Internal application of 1 mM cGMP, on the other hand, had no effect on the amplitude of either current. The amplitude of these inhibitory currents changed slightly during 20 min of patch-clamp recording. Internal perfusion of the neurons with 1 microM okadaic acid, a phosphatase inhibitor, induced potentiation in both currents. The amplitude of GABA(A) and glycine currents recorded with 1 mM internal CaCl2 and 10 mM EGTA (10 nM free Ca2+) decayed by less than 30% of control. Increasing the CaCl2 concentration to 10 mM (34 microM free Ca2+) induced a transient potentiation of the GABA(A) current. A strong depression of current amplitude was found with longer times of dialysis. The glycine current, on the contrary, was unchanged by increasing the intracellular Ca2+ concentration. Activation of G proteins with internal FAl4- induced an inhibition of the GABA(A) current, but potentiated the amplitude of the strychnine-sensitive Cl- current. These results indicate that GABA(A) and glycine receptors are differentially regulated by activation of protein kinases, G proteins and Ca2+. This conclusion supports the existence of selectivity in the intracellular regulation of these two receptor types.
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PMID:Differential intracellular regulation of cortical GABA(A) and spinal glycine receptors in cultured neurons. 937 87

Visual excitation in rhabdomeric photoreceptors is thought to be mediated by activation of a light-regulated phospholipase C (PLC) and the consequent hydrolysis of phosphatidylinositol bisphosphate. Whereas much attention has been devoted to inositol trisphosphate (IP3) production and intracellular Ca2+ release, little is known about the possible role of the DAG branch in the generation of the light response. We have tested the effect of chemically distinct surrogates of DAG on isolated Lima photoreceptors. Application of the phorbol ester PMA (0.5-10 microM) or the alkaloid (-)-indolactam (20-100 microM) from a holding potential of -50 mV elicited an inward current, several hundred picoamperes in amplitude, accompanied by a pronounced increase in membrane conductance. The stereoisomers 4alpha-PMA and (+)-indolactam were both inactive, arguing for the specificity of the effects. Elevation of cytosolic Ca2+ by intracellular dialysis accelerated this current, whereas chelerythrine antagonized it, suggesting the involvement of PKC. The reversal potential of the membrane current induced by PKC activators was approximately +10 mV; replacement of extracellular Na with impermeant N-methyl-D-glucamine decreased its amplitude and shifted the reversal potential in the negative direction. Stimulation by PMA and (-)-indolactam was accompanied by a pronounced depression of light responsiveness; conversely, steady illumination reduced the size of the current elicited by these PKC activators. Taken together, these results support the notion that the DAG branch of the PLC cascade, in addition to its suggested participation in visual adaptation, may play a role in the activation of the photoresponse or a component thereof, probably in synergy with IP3-mediated Ca2+ release.
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PMID:Membrane current induced by protein kinase C activators in rhabdomeric photoreceptors: implications for visual excitation. 965 Dec 8

1. During block of gamma-aminobutyric acid-A-mediated inhibition, low-frequency stimulation (2 Hz, 900 pulses) to Schaffer collateral-CA1 neuron synapses of adult rat hippocampus induced an N-methyl-D-aspartate receptor-independent, postsynaptic Ca2+-dependent depression of synaptic strength (long-term depression; LTD). 2. Ratio imaging with fura-2 revealed moderate dendritic [Ca2+] increases (approximately 500 nM) during only the initial approximately 30 s of the 7.5 min stimulation period. Conditioning for 30 s was, however, insufficient to induce LTD. 3. The [Ca2+] changes were insensitive to the metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). MCPG, however, completely blocked LTD when present during conditioning. 4. The [Ca2+] changes were abolished by postsynaptic hyperpolarization (-110 mV at the soma). Hyperpolarizing neurons to -110 mV during conditioning significantly attenuated LTD induction. 5. LTD induction was also blocked by the postsynaptic presence of the protein kinase C inhibitor peptide PKC(19-36). 6. These results suggest that LTD induction in adult hippocampus by prolonged low-frequency stimulation depends on both a rapid Ca2+ influx through voltage-sensitive channels and synaptic stimulation of mGluRs which may be coupled to phospholipase C.
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PMID:Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus. 971 58

The aim of this study was to investigate whether the previously observed adaptive changes in the monoaminergic receptors in post-mortem brains of depressed suicide victims are associated with alteration in some functional proteins involved in serotonergic neuronal signalling, namely PKC and GAP-43. Selected regions from ten brains of antidepressant-free depressed suicide victims and ten matched controls were used to examine the levels of GAP-43 protein, GAP-43 mRNA and PKC isoenzymes by Western blotting with monoclonal antibodies specific for these proteins. A major finding of the study was a significant decrease in GAP-43 protein levels and its mRNA expression in prefrontal cortex (BA9) (by 24% and 34%, respectively) of suicide brains compared to controls. No significant changes were found in GAP-43 protein or its mRNA in frontopolar cortex (BA10), amygdala, substantia nigra or putamen. Levels of PKC isoenzymes had a heterogenous regional distribution but were not significantly altered in any of the regions examined. Given the role of GAP-43 in the establishment and reorganization of synaptic connections, the finding of selective reduction of this protein in prefrontal cortex suggests that a dysfunctional synaptic organization in this region may be associated with depression and suicidal behaviour. This study provides the first evidence of an alteration in a protein related to the neuronal plasticity in the brain of depressed suicide victims.
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PMID:Growth-associated protein (GAP-43), its mRNA, and protein kinase C (PKC) isoenzymes in brain regions of depressed suicides. 977 74

1. Reactive oxygen species are known for their role in neurotoxicity. However, recent studies indicate that reactive oxygen species also play a role in cell function under physiological conditions. 2. Both superoxide and hydrogen peroxide alter the activity of various protein kinases and protein phosphatases, some of which are involved in hippocampal synaptic plasticity. Specifically, the activity of protein kinase C, extracellular-regulated kinase 2, and a protein tyrosine kinase(s) is increased in the presence of these reactive oxygen species, whereas the activity of protein phosphatases 2A and 2B, and a protein tyrosine phosphatase(s) is decreased. 3. Protein kinase C, extracellular-regulated kinase 2, and protein tyrosine kinases critically participate in the induction and/or early expression of long-term potentiation at glutamatergic synapses in hippocampus. Protein phosphatases 2A and 2B participate in the induction and/or early expression of long-term depression at these synapses. 4. Treatment of hippocampal slices with scavengers of either superoxide or hydrogen peroxide prevents the full expression of long-term potentiation. Long-term potentiation in hippocampus also is attenuated in transgenic mice that overexpress Cu/Zn superoxide dismutase. 5. The link between reactive oxygen species and long-term potentiation may be the activating effect on protein kinases. The inhibiting effect of reactive oxygen species on protein phosphatases may also contribute to long-term potentiation. 6. The authors hypothesize that reactive oxygen species play a critical role in hippocampal long-term potentiation by favoring the activation of a protein kinase over a protein phosphatase signaling cascade.
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PMID:Modulation of protein kinases and protein phosphatases by reactive oxygen species: implications for hippocampal synaptic plasticity. 1037 23


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