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)

Tricyclic antidepressants (e.g., imipramine, desipramine) are currently used in the treatment of mood disorders such as depression. At the cellular level they inhibit the re-uptake of the exocytosed monoamines serotonin and noradrenaline. However, they also stimulate phospholipase C activity and the production of the second messenger inositol 1,4,5-trisphosphate. Since phospholipase C activation can also lead to the production of the protein kinase C activator diacylglycerol, we have undertaken experiments to see whether acutely applied desipramine could change the synaptic strength of neurons in a protein kinase C-dependent manner. Experiments performed with cultured hippocampal neurons dissociated from neonatal rats revealed that desipramine rapidly enhanced the spontaneous vesicular release of glutamate. This was observed by measuring the frequency of tetrodotoxin-resistant spontaneous excitatory postsynaptic currents. Analysis of amplitude distribution histograms indicated a presynaptic site of action. The protein kinase inhibitor staurosporine and down-regulation of protein kinase C activity greatly reduced the desipramine-dependent enhancement of the frequency of tetrodotoxin-resistant spontaneous excitatory postsynaptic currents. This presynaptic modulation requires SNARE proteins because cleavage of SNAP-25 with the botulinum neurotoxin A strongly reduced the desipramine-induced glutamate release. Thus, acute applications of desipramine stimulated the ongoing neurotransmitter release pathway, probably by activating protein kinase C. Our data indicate that tricyclic antidepressant drugs not only act on serotoninergic and/or noradrenergic cells but can also modify the activity of glutamatergic neurons.
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PMID:Acute application of the tricyclic antidepressant desipramine presynaptically stimulates the exocytosis of glutamate in the hippocampus. 1021 74

Dopamine, acting at a D1-like receptor, depresses the release of glutamate in the nucleus accumbens (NAcc) in brain slices, thereby reducing the amplitude of the excitatory postsynaptic current (EPSC). This effect depends upon an inhibitory feedback action of adenosine, liberated following facilitation of postsynaptic NMDA receptors by D1 receptor activation, an action independent of adenylyl cyclase stimulation or cyclic AMP-dependent protein kinase (PKA; Harvey, J., Lacey, M.G., 1997. J. Neurosci. 17, 5271). Using whole-cell recording from NAcc neurones, the dopamine depression of the EPSC was blocked by pre-treatment of brain slices with the selective protein kinase C (PKC) inhibitor Ro 32-0432, but only minimally attenuated by intracellular dialysis of single cells with Ro 32-0432 in the recording pipette. With synaptic transmission blocked by tetrodotoxin, inward currents caused by application of NMDA were enhanced by the D1 receptor agonist SKF 81297A in half the cells tested. In a separate population of cells dialysed intracellularly with Ro 32-0432, SKF 81297A was without effect on NMDA current amplitude. These findings indicate a functional role for phospholipase C-coupled D1-like receptors in both modulating synaptic transmission in NAcc and potentiating NMDA receptors on a subset of NAcc neurones, via PKC activation.
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PMID:Modulation by dopamine D1-like receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. 1021 63

Growth factor receptors provide a major mechanism for the activation of the nonreceptor tyrosine kinase c-Src, and this kinase in turn up-regulates the activity of N-methyl-D-aspartate (NMDA) receptors in CA1 hippocampal neurons (1). Unexpectedly, applications of platelet-derived growth factor (PDGF)-BB to cultured and isolated CA1 hippocampal neurons depressed NMDA-evoked currents. The PDGF-induced depression was blocked by a PDGF-selective tyrosine kinase inhibitor, by a selective inhibitor of phospholipase C-gamma, and by blocking the intracellular release of Ca(2+). Inhibitors of cAMP-dependent protein kinase (PKA) also eliminated the PDGF-induced depression, whereas a phosphodiesterase inhibitor enhanced it. The NMDA receptor-mediated component of excitatory synaptic currents was also inhibited by PDGF, and this inhibition was prevented by co-application of a PKA inhibitor. Src inhibitors also prevented this depression. In recordings from inside-out patches, the catalytic fragment of PKA did not itself alter NMDA single channel activity, but it blocked the up-regulation of these channels by a Src activator peptide. Thus, PDGF receptors depress NMDA channels through a Ca(2+)- and PKA-dependent inhibition of their modulation by c-Src.
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PMID:Platelet-derived growth factor receptor-induced feed-forward inhibition of excitatory transmission between hippocampal pyramidal neurons. 1052 46

Previously, we have found that activation of mGlu receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-DHPG, can induce long-term depression (LTD) in the CA1 region of the hippocampus and that, once established, this synaptic depression can be reversed by application of the mGlu receptor antagonist, (S)-MCPG [Palmer et al., 1997. Neuropharmacology 36, 1517-1532]. We have started to investigate the signal transduction mechanisms involved in these effects. Group I mGlu receptors couple to phospholipase C and therefore can activate protein kinase C and mobilise Ca2+ from intracellular stores. However, neither protein kinase C inhibitors (chelerythrine or Ro 31-8220) nor agents which deplete intracellular Ca2+ stores (thapsigargin or cyclopiazonic acid) were able to prevent DHPG-induced LTD. Furthermore, the ability of MCPG to reverse DHPG-induced LTD was not prevented by these compounds. These results suggest that it is unlikely that DHPG-induced LTD, or its reversal by MCPG, is produced via activation of either protein kinase C or by release of Ca2+ from intracellular stores.
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PMID:An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus. 1053 Aug 20

1. Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2. The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3. The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4. Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) channel also inhibit the corticosterone-induced gene transcription. 6. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8. Imipramine decreases binding of corticosterone-receptor complex to DNA. 9. It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.
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PMID:Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism. 1090 80

Low-frequency stimulation of primary afferent Adelta-fibers can induce long-term depression of synaptic transmission in rat superficial spinal dorsal horn. Here, we have identified another form of long-term depression in superficial spinal dorsal horn neurons that is induced by specific group I but not group II metabotropic glutamate receptor (mGluR) agonists. Synaptic strength between Adelta-fibers and dorsal horn neurons was examined by intracellular recordings in a spinal cord-dorsal root slice preparation from young rat. In the presence of bicuculline and strychnine, bath application of (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) or the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) but not the specific group II mGluR agonist (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) for 20 min produced an acute and a long-term depression of synaptic strength. Bath application of the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid did not affect these depressions by (1S,3R)-ACPD. After pre-incubation of slices with pertussis toxin, a G-protein inhibitor, (1S,3R)-ACPD still induced acute and long-term depressions. The phospholipase C inhibitor U73122 stereoselectively blocked the induction of long-term depression without affecting acute synaptic inhibition. This study demonstrates that, in the spinal cord, direct activation of group I mGluRs that are coupled to phospholipase C through pertussis toxin-insensitive G-proteins induces a long-term depression of synaptic strength. This may be relevant to the processing of sensory information in the spinal cord, including nociception.
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PMID:Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn. 1097 7

Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) is the substrate for phosphoinositide-phospholipase C (PLC) and is required for the function of several cardiac cell plasma membrane (sarcolemma, SL) proteins. PtdIns 4,5-P2 is synthesized in the SL membrane by coordinated and successive actions of PtdIns 4-kinase and PtdIns 4-phosphate 5-kinase. These kinases and the generation of PtdIns 4,5-P2 may be a factor in the cardiac dysfunction during pathophysiological conditions of oxidative stress. Therefore, we examined the effects of different reactive oxygen species (ROS) on the kinases' activities and subsequent generation of PtdIns 4,5-P2. Exposure to the xanthine-xanthine oxidase-ROS generating system significantly reduced both SL kinase activities. Superoxide dismutase did not prevent this inhibition; however, catalase significantly prevented the xanthine-xanthine oxidase induced inhibition. Treatment of SL with hydrogen peroxide (H2O2) resulted in inhibition of both the kinases, which was prevented by catalase and dithiothreitol (DTT). Hypochlorous acid also inhibited both the kinases, which was prevented by DTT. Deferoxamine (an iron chelator) and mannitol (an *OH scavenger) did not modify the H2O2-induced depression of the kinases, eliminating any role of *OH. Furthermore, the IC50 of H2O2 on PtdIns 4-kinase and PtdIns 4-P 5-kinase was 27 and 81 microM, respectively. In addition, inclusion of reduced glutathione in the assay of the kinases in the absence of H2O2 did not affect the activities of the kinases; however, oxidized glutathione induced a significant depression. Also, a significant decline of the PtdIns 4-kinase and PtdIns 4-P 5-kinase activities due to changing of the redox ratio was observed. Thiol modifiers (N-ethylmaleimide, methyl methanethiosulfonate, or p-chloromercuriphenylsulfonic acid) were detected to depress the kinases' activities, which were substantially prevented by DTT. The results suggest that functionally critical thiol groups may be associated with PtdIns 4-kinase and PtdIns 4-P 5-kinase and that changes of their redox state by ROS can impair their activities, which may be an important factor in the oxidant-induced cardiac dysfunction.
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PMID:Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma. 1105 Oct 96

Metabotropic glutamate receptors (mGluRs) modulate neuronal function via different transduction mechanisms that are either dependent or independent on G-protein function. Here we investigated, using whole cell patch-clamp recordings in combination with fluorimetric measurements of intracellular calcium concentration ([Ca(2+)](i)), the metabolic pathways involved in the responses induced by group I mGluRs in dopamine neurons of the rat midbrain. The inward current and the [Ca(2+)](i) increase caused by the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 100 microM) were permanently activated and subsequently abolished in cells loaded with the nonhydrolizable GTP-analogue GTP-gamma-S (600 microM). In addition, when GDP-beta-S (600 microM) was dialyzed into the cells to produce the blockade of the G proteins, the DHPG-dependent responses were reduced. When the tissue was bathed with the phospholipase C inhibitor 1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]exyl]-1H-pyrrole-2,5-dione (10 microM), the DHPG-induced calcium transients slightly diminished but the associated inward currents were not affected. Interestingly, a substantial depression of the DHPG-induced inward current and transient increase of [Ca(2+)](i) was caused by the protein tyrosine kinase inhibitors tyrphostin B52 (40 microM) and 4',5,7-trihydroxyisoflavone (genistein; 40 microM), whereas genistein's inactive analogue 4',5,7-trihydroxyisoflavone-7-glucoside (40 microM) was ineffective. The blockade of the Src family of tyrosine kinase by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (20 microM), mitogen-activated protein kinase by 2'-amino-3' methoxyflavone (50 microM), and protein kinase C by staurosporine (1 microM) had no effect on the cellular responses caused by DHPG. The mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)-pyridine (10--100 microM) did not affect the actions of DHPG. Thus our results indicate that the responses, mainly mediated by mGluRs1 in dopamine neurons, are activated by intracellular mechanisms coupled to G proteins and regulated by tyrosine kinases.
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PMID:Group I mGluRs coupled to G proteins are regulated by tyrosine kinase in dopamine neurons of the rat midbrain. 1138 95

Activation of the type-1 metabotropic glutamate receptor (mGluR1) signaling pathway in the cerebellum involves activation of phospholipase C (PLC) and protein kinase C (PKC) for the induction of cerebellar long term depression (LTD). The PLC and PKC isoforms that are involved in LTD remain unclear, however. One previous study found no change in LTD in PKCgamma-deficient mice, thus, in the present study, we examined cerebellar LTD in PLCbeta4-deficient mice. Immunohistochemical and Western blot analyses of cerebellum from wild-type mice revealed that PLCbeta1 was expressed weakly and uniformly, PLCbeta2 was not detected, PLCbeta3 was expressed predominantly in caudal cerebellum (lobes 7-10), and PLCbeta4 was expressed uniformly throughout. In PLCbeta4-deficient mice, expression of total PLCbeta, the mGluR1-mediated Ca(2+) response, and LTD induction were greatly reduced in rostral cerebellum (lobes 1-6). Furthermore, we used immunohistochemistry to localize PKCalpha, -betaI, -betaII, and -gamma in mouse cerebellar Purkinje cells during LTD induction. Both PKCalpha and PKCbetaI were found to be translocated to the plasmamembrane under these conditions. Taken together, these results suggest that mGluR1-mediated activation of PLCbeta4 in rostral cerebellar Purkinje cells induced LTD via PKCalpha and/or PKCbetaI.
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PMID:Phospholipase Cbeta4 and protein kinase Calpha and/or protein kinase CbetaI are involved in the induction of long term depression in cerebellar Purkinje cells. 1155 22

The effects of phenylarsine oxide and a monoclonal antibody directed against type II phosphatidylinositol 4-kinase (PI4K) on the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated respiratory burst and the PI4K activity in neutrophils were investigated. Fluorescence microscopic imaging showed that the antibody labeled with IANBD amide (N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)ethylenediamine) could enter into the cytosol possibly by endocytosis. It was found that the antibody inhibited the fMLP-stimulated respiratory burst but had little effect on the phorbol myristate acetate-activated respiratory burst in neutrophils, whereas phenylarsine oxide inhibited both. It was found that even at higher concentration, the antibody could not completely inhibit the cell response. Using cells preincubated with human immunoglobulin G of the same concentration as the control, the maximal inhibition of the fMLP-stimulated respiratory burst by the antibody against type II PI4K was found to be about 70%, whereas the PI4K activity was inhibited by only about 40%. The discrepancy in depressing the cell response and the enzyme activity may be the result of depletion of the phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate pools during the incubation of cells with the antibody. Both the 40% inhibition of PI4K activity and 70% depression of the respiratory burst by the type II PI4K antibody may imply that at least 40% of the phosphatidylinositol 4,5-biphosphate was synthesized promptly by all forms of PI4K and phosphatidylinositol-4-phosphate 5-kinase in the fMLP-activated cells. The results suggest that PI4K plays a central role in either phospholipase C or PI3K signaling and that PI3K, PI4K, and phosphatidylinositol 4-phosphate 5-kinase must be considered as an integrated family for the phosphatidylinositol 3,4,5-trisphosphate initiated signaling.
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PMID:Inhibition of phosphatidylinositol 4-kinase results in a significant reduced respiratory burst in formyl-methionyl-leucyl-phenylalanine-stimulated human neutrophils. 1159 57


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