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)

Glutamate-gated ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A-D), AMPA (GluR1-4) and KA (GluR5-7, KA1, KA2) receptors. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation and long-term depression. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.
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PMID:Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. 809 92

Interleukin-1 beta depresses the voltage-gated Ca2+ channel currents in acutely dissociated guinea-pig hippocampal CA1 neurons. This depression is observed with pathophysiological concentrations found in the cerebrospinal fluid (> or = 1.0 pg interluekin-1 beta/10 microliters). Interleukin-1 receptor antagonist (in concentrations 25-fold higher than interleukin-1 beta) completely blocked the interleukin-1 beta-induced depression of the Ca2+ channel current. This suggests that interleukin-1 beta action is through a specific interaction with an interleukin-1 membrane receptor site. The application of other cytokines and growth factors (interleukin-6, epidermal growth factor, and basic fibroblast growth factor), or bacterial lipopolysaccharide (endotoxin) had no effect, indicating specificity of action of interleukin-1 beta. The depression of the Ca2+ channel current by interleukin-1 beta was prevented by the extracellular application of pertussis toxin, and by the intracellular application of GDP[beta S], H-7, staurosporine or bisindolylmaleimide. Application of phorbol 12-myristate 13-acetate also depressed the Ca2+ channel current, but this phorbol ester-induced depression was not additive to that induced by interleukin-1 beta. These results suggest mediation of interleukin-1 beta action through a pertussis toxin-sensitive G-protein coupled interleukin-1 receptor associated with the activation of protein kinase C. The depression of the Ca2+ channel current by interleukin-1 beta may be involved in the regulation of neuronal excitability during pathological conditions and in the induction and/or progression of neurodegenerative processes.
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PMID:Interleukin-1 beta inhibits Ca2+ channel currents in hippocampal neurons through protein kinase C. 813 77

Previously the plasma membrane-bound or purified Ca(2+)-translocation ATPase (Ca2+ pump) was found to be activated and phosphorylated by protein kinase C in vitro (K. K. W. Wang et al. 1991, J. Biol. Chem. 266, 9078-9085). We now show that in intact human erythrocytes phorbol-12-myristate 13-acetate (PMA), a known stimulator of protein kinase C, decreases the amplitude of the intracellular calcium ([Ca2+]i) transient induced by 2.5 microM CaCl2 and 10 microM A23187. Since PMA did not affect Ca2+ influx, the decrease in amplitude was most likely due to the stimulation of the Ca2+ pump, the major mechanism of calcium extrusion in these cells. The effect was dose-dependent, the maximum decrease in amplitude (33%) occurring at 1 microM PMA. The depression of the [Ca2+]i transient was further enhanced by the phosphatase inhibitor okadaic acid. It was reversed by the protein kinase C inhibitor staurosporine and could not be mimicked by inactive PMA analogues. In erythrocytes labeled with [32P]orthophosphate, PMA treatment phosphorylated the Ca(2+)-ATPase in a dose-dependent manner. The phosphorylation was inhibited by staurosporine and was slightly enhanced by okadaic acid. Changes in lipid phosphorylation and content were studied under the same conditions in intact cells. The turnover of 32P and lipid phosphate in phosphatidylinositol 4,5-bisphosphate (PIP2) was inhibited by 1 mM adriamycin, concomitant with an increased amplitude of the [Ca2+]i transient. The PIP2 content and its 32P radioactive did not, however, change with PMA stimulation. We conclude that while both protein kinase C and polyphosphoinositides are regulators of Ca(2+)-ATPase activity in the intact human erythrocyte, stimulation of the enzyme activity by PMA is predominantly protein kinase C-mediated.
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PMID:Regulation of the activity and phosphorylation of the plasma membrane Ca(2+)-ATPase by protein kinase C in intact human erythrocytes. 821 16

Stress, such as heat-shock, hypoxia and hypoglycemia, inhibits the initiation of protein synthesis. The effects of heat-shock on protein synthesis, eucaryotic initiation factor 2 (eIF-2) activity, protein kinase C (PKC), and casein kinase II (CKII) activities were studied in primary cortical neuronal cultures. In neurons exposed to heat-shock at 44 degrees C for 20 min, protein synthesis is inhibited by more than 80%, and is accompanied by a 60% decrease in eIF-2 activity. Steady state PKC and CK II activities were not affected by heat-shock. Vanadate (200 microM), a protein phosphotyrosine phosphatase inhibitor, partially prevented the depression of eIF-2 activity during heat-shock, and increased CKII activity by 90%. In contrast, staurosporine (62nM), a protein kinase C inhibitor, did not affect eIF-2 activity. We conclude that heat-shock causes a change in the phosphorylation/dephosphorylation of regulatory proteins leading to a depressed eIF-2 activity and protein synthesis in neurons.
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PMID:Heat-shock inhibits protein synthesis and eIF-2 activity in cultured cortical neurons. 823 16

The exposure of NIH 3T3 fibroblast cells to 254 nm UV radiation resulted in a temporary depression of DNA synthesis and inhibition of 80 kDa protein phosphorylation. This inhibition of protein phosphorylation was correlated with decreased protein kinase C activity in the membrane fractions of UV-damaged cells. The inositol triphosphate contents measured, by the competitive binding assay using bovine adrenal binding protein, showed 80% reduction in the fibroblasts treated with 15 J/m2 of UV light. The intracellular diacylglycerol concentration was also markedly reduced in UV-damaged cells. The results suggest that UV light causes acute reductions of inositol triphosphate and diacylglycerol contents in cells along with decreases in membrane protein kinase C activity, which leads to the inhibition of phosphorylation of an acidic protein of 80 kDa.
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PMID:Inhibition of 80 kDa protein phosphorylation by short-wavelength UV light in NIH 3T3 cells. 824 28

1. The effects of protein kinase C (PKC) activators and inhibitors on the mechanisms regulating cytosolic Ca2+ homeostasis in dissociated bovine parathyroid cells loaded with fura-2 were examined. 2. Stepwise increases in the concentration of extracellular Ca2+ (from 0.5 to 2 or 3 mM) elicited transient followed by sustained increases in the concentration of intracellular free Ca2+ ([Ca2+]i). Cytosolic Ca2+ transients reflected the mobilization of intracellular Ca2+ and influx of extracellular Ca2+ whereas sustained increases in [Ca2+]i resulted from the influx of extracellular Ca2+. Brief (1-2 min) pretreatment with phorbol myristate acetate (PMA) shifted the concentration-response curve for extracellular Ca(2+)-induced cytosolic Ca2+ transients to the right without affecting the maximal response. Cytosolic Ca2+ transients elicited by extracellular Mg2+ were similarly affected by PMA. 3. These effects of PMA were mimicked by various other activators of PKC with the rank order of potency PMA > phorbol dibutyrate > bryostatin , > (-)indolactam V > mezerein. Isomers or analogues of these compounds that do not alter PKC activity (4 alpha-phorbols and (+)indolactam V) did not alter [Ca2+]i. 4. PKC activators depressed evoked increases in [Ca2+]i when influx of extracellular Ca2+ was blocked with Gd3+. Cytosolic Ca2+ transients elicited by extracellular Mg2+ in the absence of extracellular Ca2+ were similarly inhibited by PKC activators. Activation of PKC thus inhibits the mobilization of intracellular Ca2+ elicited by extracellular divalent cations. 5. Increases in the concentration of extracellular Ca2+ caused corresponding increases in the formation of [3H]inositol 1,4,5-trisphosphate ([3H]InsP3). Pretreatment with PMA shifted the concentration-response curve for extracellular Ca(2+)-induced [3H]InsP3 formation to the right without affecting the maximal response. 6. PKC activators also caused some depression of steady-state increases in [Ca2+]i elicited by extracellular Ca2+. In contrast, PMA did not affect increases in [Ca2+]i elicited by ionomycin or thapsigargin. 7. Ba2+ was used to monitor divalent cation influx. PMA decreased the rate of rise of the fluorescent signal elicited by extracellular Ba2+. 8. All these effects of PKC activators on [Ca2+]i were blocked or reversed by staurosporine at concentrations (30-100 nM) that inhibited PKC activity in parathyroid cells. Staurosporine alone potentiated cytosolic Ca2+ responses evoked by submaximal concentrations of extracellular divalent cations. 9. PKC thus depresses both the mobilization of intracellular Ca2+ and the influx of extracellular Ca2+ in parathyroid cells. The effects on [Ca2+]i provide evidence for a Ca2+ receptor on the surface of parathyroid cells that uses transmembrane signalling mechanisms common to some other Ca(2+)-mobilizing receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytosolic calcium homeostasis in bovine parathyroid cells and its modulation by protein kinase C. 825 4

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.
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PMID:Modified hippocampal long-term potentiation in PKC gamma-mutant mice. 826 9

We have previously presented indirect in vivo evidence for the involvement of islet acid glucan-1,4-alpha-glucosidase (acid amyloglucosidase), a lysosomal glucose-producing enzyme, in certain insulin secretory processes. In the present in vitro and in vivo investigation, we studied whether differential changes in islet acid amyloglucosidase activity would be related to the insulin secretory response induced by two mechanistically different secretagogues, the sulphonylurea derivative, glibenclamide and the acetylcholine receptor agonist, carbachol. It was observed that the selective alpha-glucosidehydrolase inhibitors emiglitate and acarbose markedly reduced glibenclamide-induced insulin release from isolated islets. Insulin release stimulated by carbachol or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate), was not inhibited. Basal insulin secretion was unaffected by emiglitate and acarbose. Further, pretreatment of mice with emiglitate resulted in a marked reduction of the in vivo insulin response to glibenclamide. Moreover, in vivo pretreatment with purified fungal amyloglucosidase ('enzyme replacement'), a procedure known to increase islet amyloglucosidase activity, greatly enhanced the insulin response to i.v. glibenclamide. This insulin release was accompanied by a marked depression of the blood glucose levels. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after carbachol. The data strongly suggest that islet acid amyloglucosidase is involved in the insulin secretory processes induced by glibenclamide but not in those involving stimulation of muscarinic receptors or direct activation of protein kinase C. The results also indicate separate or at least partially separate pathways for insulin release induced by glibenclamide and cholinergic stimulation.
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PMID:Changes in islet glucan-1,4-alpha-glucosidase activity modulate sulphonylurea-induced but not cholinergic insulin secretion. 827 68

1. The electrophysiological action of the mu-opioid receptor-preferring agonist D-Ala2, MePhe4, Met(O)5-ol-enkephalin (FK 33-824) on synaptic transmission has been studied in area CA3 of organotypic rat hippocampal slice cultures. 2. FK 33-824 (1 microM) had no effect on the amplitude of pharmacologically isolated N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated EPSPs. 3. FK 33-824 (10 nM to 10 microM) reduced the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) that were elicited in pyramidal cells with local stimulation after pharmacological blockade of excitatory amino acid receptors. This effect was reversible, dose-dependent, and sensitive to naloxone and the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP). FK 33-824 at 1 microM caused a mean reduction in the amplitude of the monosynaptic IPSP of 70%. 4. Neither delta- nor kappa-receptor-preferring agonists had any effect on excitatory or inhibitory synaptic potentials. 5. The disinhibitory action of FK 33-824 was blocked by incubating the cultures with pertussis toxin (500 ng/ml for 48 h) or by stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu, 0.5 microM). 6. The depression of monosynaptic IPSPs by FK 33-824 was unaffected by extracellular application of the K+ channel blockers Ba2+ or Cs+ (1 mM each). 7. FK 33-824 produced a decrease in the frequency of miniature, action potential-independent, spontaneous inhibitory synaptic currents (mIPSCs) recorded with whole-cell voltage-clamp techniques, but did not change their mean amplitude. Application of the Ca2+ channel blocker Cd2+ (100 microM) or of nominally Ca(2+)-free solutions did not alter either the frequency and amplitude of mIPSCs or the reduction of mIPSC frequency induced by FK 33-824. 8. The effect of FK 33-824 on spontaneous mIPSCs was prevented by naloxone, and by incubation of cultures with pertussis toxin. 9. These results indicate that mu-opioid receptors decrease GABA release presynaptically by a G protein-mediated inhibition of the vesicular GABA release process, and not by changes in axon terminal K+ or Ca2+ conductances that are sensitive to extracellular Ba2+, Cs+ or Cd2+.
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PMID:Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. 830 42

Lithium, an effective treatment for mania and the prevention of recurrent episodes of both mania and depression in patients with manic depressive illness, exerts multiple biochemical effects. However, any clinically relevant site of action of lithium must occur at therapeutic concentrations attained in the brain of patients and must account for the lag period accompanying onset of action as well as effects persisting beyond discontinuation of treatment. This monovalent cation acts as a potent uncompetitive inhibitor in the receptor-coupled breakdown of inositol phospholipids, resulting in a relative depletion of inositol and an alteration in the generation of diacylglycerol, an endogenous activator of protein kinase C. In our laboratory, we are examining the action of chronically administered lithium on posttranslational modification of specific phosphoproteins involved in regulating signal transduction in the brain. We have found that chronic, but not acute, administration of lithium in rats markedly reduces a major phosphoprotein substrate of protein kinase C in the hippocampus, an effect that persists beyond the cessation of lithium treatment. This protein, myristoylated alanine-rich C kinase substrate ("MARCKS"), is implicated in synaptic neurotransmission, calcium regulation, and cytoskeletal restructuring. These findings have relevance for the long-term action of lithium in stabilizing an underlying dysregulation in the brain and may move us closer to formulating a molecular basis of manic depressive illness.
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PMID:Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness. 831 12


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