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)

Increased protein tyrosyl phosphorylation in response to growth factors has been assumed to be solely due to activation of protein tyrosine kinases (PTKs). We report that total cellular protein tyrosine phosphatase (PTPase) activity declined in MDA-MB 468 breast carcinoma cells exposed to epidermal growth factor (EGF). The PTPase activity decreased with concentration as well as with time of EGF incubation. As EGF induces increases in intracellular Ca2+ concentrations and such changes may result in depression of PTPase activity, we treated cells with the calcium ionophore A 23187. Increases in calcium induced by the ionophore resulted in activation of cellular PTPases as indicated by increased dephosphorylation of tyrosine phosphorylated EGFR by cellular lysates. Thus, both the extracellular ligand EGF and the intracellular messenger Ca2+ were shown to modulate cellular PTPase activity in MDA-MB 468 breast carcinoma cells. However, EGF-induced decreases in PTPase activity cannot be attributed to EGF-induced increases in intracellular Ca2+ levels.
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PMID:Role of intracellular Ca2+ in the epidermal growth factor induced inhibition of protein tyrosine phosphatase activity in a breast cancer cell line. 768 60

Recently there has been considerable conjecture in the literature concerning a possible relationship between stress, depression and bereavement, and carcinoma. We shall propose a causal model in which the relationship between stress, depression and carcinoma is clarified. This relationship is grounded on dysregulation of the inflammatory cytokines in stress and depression. Stress is associated with increased expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), and reduced expression of IL-2, interferon-gamma (IFN-gamma), major histocompatability complex (MHC) class II molecules and natural killer cell activity (NKA). Depression is associated with elevated IFN-gamma and IL-1 beta, downregulated IL-2, and reduced NKA. Most organ-related carcinomas are associated with elevated TNF-alpha, which inhibits the activity of protein tyrosine phosphatase (PTPase), the enzyme that initiates activation of the MHC class I pathway. Sustained elevation of TNF-alpha inhibits the activity of PTPase which results in diminished expression of the MHC class I antigen on the cell surface and thus, malignant cells escape immune surveillance. Therefore, stress and depression can foster tumor progression by means of inhibiting the expression of MHC class I and II molecules and through the reduction of NKA.
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PMID:An immunological model connecting the pathogenesis of stress, depression and carcinoma. 982 37

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

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
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PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

We examined the effects of two protein tyrosine phosphatase inhibitors on the induction of synaptic plasticity in CA1 slices of rat hippocampus. Field potential recordings were made in stratum radiatum in response to stimulation of the Schaffer collateral afferents. Bath application of the tyrosine phosphatase inhibitors sodium orthovanadate or phenylarsine oxide for 30 min had little effect on basal synaptic transmission but blocked the induction of both long-term potentiation (LTP) and homosynaptic long-term depression (LTD). LTP could be partially recovered, and LTD fully recovered, when conditioning stimulation was given in conditions of reduced synaptic inhibition. The block of both forms of synaptic plasticity by the phosphatase inhibitors correlated with a concurrent depression of the N-methyl-D-aspartate (NMDA) receptor-mediated potential, as measured both extracellularly and intracellularly. This depression, which was also induced by peroxyvanadate, required synaptic stimulation to be induced, and was tyrosine kinase-dependent. Our results suggest that tyrosine phosphorylation of as yet unidentified proteins is responsible for a novel activity-dependent depression of NMDA receptor function that inhibits synaptic plasticity.
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PMID:Tyrosine phosphorylation-dependent inhibition of hippocampal synaptic plasticity. 1097 10

Calcineurin is ubiquitously distributed phosphatase in the central nervous system. It has various functions, such as modulating channel properties, suppressing transmitter release, and activating transcript factors. Recently the critical role of calcineurin on synaptic plasticity, especially long-term depression, was reported, although the precise mechanism underlying LTD induction is still being debated. Calcineurin, activated by the Ca2+ influx mainly through the NMDA channel and calmodulin, dephosphorylates inhibitor-1, which suppresses PP1 activity. Thus the activation of calcineurin enhances PP1, resulting in facilitating the process leading to LTD induction. The activation of calcineurin modifies the threshold of LTP induction. A recent interesting finding is the gating mechanism from the early phase of LTP to the late phase of LTP by calcineurin activity, a process regulated by cAMP. We have reported a new type of LTD, which is suppressed by calcineurin that is dependent on group 2 mGluR receptor activity. According to the result using whole cell study with a patch pipette, including FK-506, an antagonist of calcineurin, the induction site of this LTD is presynaptic, which defers from conventional LTD. We have also discussed the involvement of murine protein tyrosine phosphatase (MPTP) in LTD induction in the hippocampal CA1 region by using an MPTP delta knockout mouse.
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PMID:[The role of calcineurin on the induction of synaptic plasticity]. 1132 44

A form of long-term depression (LTD) of synaptic transmission can be induced by bath application of the group I metabotropic glutamate (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). The mechanisms responsible for the induction and expression of DHPG-induced LTD in the CA1 region of the hippocampus are currently the subject of intense investigation. Here we show that two protein tyrosine kinase (PTK) inhibitors (10 microM lavendustin A or 30 microM genistein) have little effect on DHPG-induced LTD. In contrast two protein tyrosine phosphatase (PTP) inhibitors (1 mM orthovanadate or 15 microM phenyl-arsine oxide) significantly inhibited DHPG-induced LTD. These data suggest that DHPG-induced LTD involves activation of a protein tyrosine phosphatase.
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PMID:Tyrosine dephosphorylation underlies DHPG-induced LTD. 1221 71

Alpha7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of alpha7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these receptors are amenable to modulation by tyrosine phosphorylation. In both Xenopus oocytes and rat hippocampal interneurons, brief exposure to a broad-spectrum protein tyrosine kinase inhibitor, genistein, specifically and reversibly potentiated alpha7 nAChR-mediated responses, whereas a protein tyrosine phosphatase inhibitor, pervanadate, caused depression. Potentiation was associated with an increased expression of surface alpha7 subunits and was not accompanied by detectable changes in receptor open probability, implying that the increased function results from an increased number of alpha7 nAChRs. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis was shown to be a plausible mechanism for the rapid delivery of additional alpha7 nAChRs to the plasma membrane. Direct phosphorylation/dephosphorylation of alpha7 subunits was unlikely because mutation of all three cytoplasmic tyrosine residues did not prevent the genistein-mediated facilitation. Overall, these data are consistent with the hypothesis that the number of functional cell surface alpha7 nAChRs is controlled indirectly via processes involving tyrosine phosphorylation.
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PMID:Rapid upregulation of alpha7 nicotinic acetylcholine receptors by tyrosine dephosphorylation. 1581 2

Acid phosphatase locus 1 (ACP 1 ) or cytosolic low molecular weight protein tyrosine phosphatase is a polymorphic enzyme that can hydrolyze phosphotyrosine-containing peptides of the human insulin receptor and of band 3 protein. High-activity ACP 1 may favor an increase in serum glucose concentration through a depression of insulin action and through inactivation of aldolase, phosphofructokinase, and glyceraldehyde-3-phosphate dehydrogenase induced by dephosphorylation of band 3 protein. In diabetic subjects, we have previously reported lower serum glucose concentration in subjects with low-activity ACP 1 A and AB phenotypes. We have now studied the relationship between serum glucose concentration and ACP 1 genotype in a sample of 137 healthy adult workers of our university. In males, serum glucose concentration is significantly higher in medium-high- than in low-activity ACP 1 genotypes. With advancing age in males, there is a progressive increase in glycemic differential between medium-high- and low-activity ACP 1 genotypes. The data suggest that normal variability of ACP 1 genotype influences serum glucose concentration in normal individuals. Such influence depends on sex and in males becomes more marked with advancing age.
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PMID:Serum glucose concentration and ACP1 genotype in healthy adult subjects. 1598 97

N-methyl-D-aspartate (NMDA)-type glutamate receptors perform critical functions during the development of the nervous system and in the initiation of synaptic plasticity. An important mechanism in setting the gain of NMDA receptors involves the stimulation of G-protein-coupled receptors (GPCRs), which through activation of protein tyrosine kinases leads to an upregulation of NMDA receptors. In contrast, little is known about how NMDA receptors are downregulated. In the present study, we characterized a signaling pathway that mediates the depression of NMDA receptor function in response to stimulation of muscarinic acetylcholine receptors. Whole-cell patch-clamp recordings obtained from CA3 pyramidal cells in organotypic slice cultures revealed that under conditions of low intracellular calcium buffering application of muscarine-depressed NMDA receptor current. The sensitivity of this response to pirenzipine indicated that the M1 acetylcholine receptor is mediating this depression. The muscarine-induced depression of NMDA current was prevented by blocking G-protein function or after depleting intracellular Ca2+ stores with cyclopiazonic acid. Inhibitors of calmodulin prevented the depression whereas blocking calcineurin enhanced the depression of NMDA currents. Blocking tyrosine phosphatase activity with pervanandate converted the muscarine-induced depression into a potentiation of NMDA currents, whereas blocking protein kinase A (H-89), Src kinase (PP2, SU6656), or PKC (GF 109203X) failed to prevent the depression of NMDA currents. As Src tyrosine kinase is known to phosphorylate and upregulate NMDA receptors, we propose that a protein tyrosine phosphatase(s) counteracting the action of Src is the final target in the mAChR-dependent inhibitory signaling cascade. Our data are consistent with a transduction cascade comprising an M1 acetylcholine receptor-->G-protein-->Ca2+ release-->calmodulin-->tyrosine phosphatase.
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PMID:Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. 1599 5


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