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)

1. Ca(2+)-activated K+ channels regulate the excitability of many nerve terminals. A Ca(2+)-activated K+ channel present in the membranes of rat posterior pituitary nerve terminals runs down following the formation of excised patches. This run-down process reflects enzymatic dephosphorylation. 2. Both Mg-ATP and the protein phosphatase inhibitor okadaic acid prevented run-down of channel activity in excised patches. The okadaic acid sensitivity suggests that run-down resulted from dephosphorylation by a type 1 protein phosphatase. 3. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) accelerated run-down by accelerating okadaic acid-sensitive dephosphorylation. GTP gamma S had no effect on the activity of the protein kinase in these patches. These results suggest a direct coupling between a G-protein and a protein phosphatase. 4. After run-down, channel activity could be restored by Mg-ATP; restoration depended on ATP hydrolysis, but did not require Ca2+ or a second messenger. Restoration of channel activity by ATP was blocked by staurosporine and 1-(5-isoquinolinylsulphonyl)-3-methylpiperizine, but not by more specific inhibitors of protein kinases. 5. Restoration of channel activity by phosphorylation was very sensitive to membrane potential; increasing the voltage by as little as 10 mV could dramatically enhance recovery. 6. Ca2+ and voltage acted synergistically to enhance phosphorylation; higher [Ca2+] permitted phosphorylation at more negative potentials. 7. During trains of high frequency stimulation under current clamp, action potentials were influenced by both the protein phosphatase and protein kinase, indicating that enzymatic modulation of channel gating occurs under physiological conditions. An important implication of these results is that voltage-dependent phosphorylation could play a role in use-dependent depression of secretion from nerve terminals.
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PMID:Phosphorylation and dephosphorylation modulate a Ca(2+)-activated K+ channel in rat peptidergic nerve terminals. 802 31

Exposure of a wide variety of cells to ionizing (X- or gamma-) irradiation results in a division delay which may have several components including a G1 block, a G2 arrest or an S phase delay. The G1 arrest is absent in many cell lines, and the S phase delay is typically seen following relatively high doses (> 5 Gy). In contrast, the G2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34cdc2 in others. Similar mechanisms are likely to be operative in the G2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays may lead to improvement in the efficacy of radiotherapy and/or chemotherapy if they can be exploited to decrease repair or increase apoptosis following exposure to those agents.
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PMID:The molecular basis for cell cycle delays following ionizing radiation: a review. 804 94

In isolated human platelets, exposure of subfraction 3 high-density lipoprotein (HDL3) binding sites to high concentrations of HDL3 (1 mg/mL) causes rapid desensitization of HDL3 (50 micrograms/mL)-stimulated breakdown of phosphatidylcholine, as shown in approximately a 70% depression of the maximal 1,2-diacylglycerol release activity by phospholipase C. This desensitization is HDL3 dose dependent (IC50, 150 +/- 20 micrograms/mL, n = 6) and time dependent (t1/2, < 30 seconds). It requires the binding of HDL3, as pretreatment of HDL3 by tetranitromethane does not cause the desensitization of HDL3-induced phospholipase C activity. Permeabilization of human platelets with 10 micrograms/mL digitonin, used to permit access of charged inhibitors to the cytosol, does not interfere with the pattern of HDL3 (1 mg/mL)-induced desensitization of HDL3 (50 micrograms/mL)-stimulated phospholipase C. Inhibitors of protein kinase C (100 mumol/L H-7 and 10 mumol/L staurosporine) markedly inhibit desensitization of HDL3-induced phospholipase C activity, whereas cAMP-dependent protein kinase inhibitor (1 mumol/L), heparin (100 nmol/L), or concanavalin A (0.25 mg/mL) were ineffective. HDL3-induced desensitization is accompanied at least by the phosphorylation of the 94- and 110-kD proteins. Inhibition of HDL3-induced desensitization by 100 mumol/L H-7 or 10 mumol/L staurosporine is characterized by a marked reduction of the phosphorylation state of these proteins in permeabilized platelets. Whereas protein kinase C inhibitors fully inhibited the phosphorylation of the 94- and 110-kD proteins, inhibitors of protein kinase A were less effective. These data establish that phosphorylation by protein kinase C represent a step in the desensitization of HDL3 binding sites in human platelets.
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PMID:Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets. 804 94

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

Contractile response, membrane activity, and protein kinase A (PKA) activity were measured on the longitudinal muscle taken from the estrogen-treated rat uterus, and the influence of Mn ion on the inhibitory effects caused by db cAMP and forskolin was investigated. Phasic contractions generated in the muscle taken from the middle portion of uterus were depressed to 48 and 83% by 30 microM db cAMP and 0.1 microM forskolin in Mg-free Krebs solution, respectively; phasic contractions were more strongly depressed by the agents in the solution containing 0.2 mM Mn. Action potentials consisted of spike and plateau components, and the duration of the plateau potential was reduced by the application of the agents; membrane activity was more strongly depressed in the presence of 0.2 mM Mn. The contractile depression caused by db cAMP was reduced and by forskolin was enhanced by pretreatment of the tissue with 0.6 mM Mn for 30 min. The PKA activity was increased by 39 and 6% of the control, when 30 microM db cAMP and 0.1 microM forskolin were applied, respectively; the PKA activity in response to db cAMP and forskolin was reduced and enhanced, respectively, when the tissues were pretreated with 0.6 mM Mn. It was proposed that Mn ions permeated into cell interior when the muscle was exposed to 0.6 mM Mn, so that the effects of the agents were differently affected. It was also shown that plateau potential dominated in the muscle taken from the ovarian portion, and the contractile inhibition caused by the agents was far weaker.
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PMID:Influence of Mn ion the action of dibutyryl cyclic AMP and forskolin on contraction, membrane response, and cyclic AMP-dependent protein kinase activity in rat myometrium. 811 57

Unipolar depression, alcoholism and suicide have become more common over the past decades. Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (p21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. This could lead not only to a predisposition to depression ('trait markers') but to neurotoxic damage, predisposed by inadequate cytosol Mg2+ levels of hypometabolism. Tyrosine, tryptophan and phenylalanine hydroxylases all require tetrahydrobiopterin (BH4) which allosterically regulates its own activity as well as that of these enzymes. Anything which impairs this cofactor could lead to overt depression in predisposed individuals, and the heterocyclic amines are being increasingly implicated. These substances are derived from fried and broiled meats, azo food dyes, soft drinks and hard candies, but particularly from cigarette and petroleum fumes. The heterocyclic amines can inhibit aromatic-l-amino-acid-decarboxylase (AADC) as well as the hydroxylases reversibly, but BH4 is inhibited noncompetitively. Thus, susceptible individuals (those with inherited defective protein kinase phosphorylation) might be 'tipped over' by chronic exposure to these neurotoxins. The rising incidence of unipolar depression-associated morbidity could be significantly linked to increasing levels of heterocyclic amines in the developed nations.
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PMID:The 'cerebral diabetes' paradigm for unipolar depression. 814 51

Coactivation of metabotropic glutamate receptors (mGluRs) and beta-adrenergic receptors causes a synergistic increase in cAMP formation in the rat hippocampus. Increases in cAMP are known to have many actions in the hippocampus via activation of cAMP-dependent protein kinase. We now report that coactivation of mGluRs and beta-adrenergic receptors induces an acute depression of EPSCs at the Schaffer collateral-CA1 synapse. Interestingly, this depression of EPSCs is dependent upon increases in cAMP levels but independent of protein kinase activity. A series of studies suggests that cAMP-mediated depression of EPSCs is dependent on metabolism of cAMP and release of adenosine or 5'-AMP into the extracellular space with resultant activation of presynaptic adenosine receptors. These studies suggest that cAMP can have local hormone-like effects in the hippocampal formation which are independent of cAMP-dependent protein kinase.
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PMID:Potentiation of cAMP responses by metabotropic glutamate receptors depresses excitatory synaptic transmission by a kinase-independent mechanism. 818 47

Deletion of the SLT2 gene of Saccharomyces cerevisiae, which codes for a homologue of MAP (mitogen-activated) protein kinases, causes an autolytic lethal phenotype in cells grown at 37 degrees C. The gene encodes domains characteristic of protein kinases, which include a lysine (at position 54) that lies 19 residues from a glycine-rich cluster, considered to be the putative ATP binding site. The ability of three mutant alleles of SLT2 generated by site-directed mutagenesis, namely E54 (glutamic acid), R54 (arginine) and F54 (phenylalanine), to complement slt2 mutants was tested. All three failed to complement the autolytic phenotype and were unable to restore growth and viability of cells. A strain obtained by transplacement of slt2-F54 also behaved as a thermosensitive autolytic mutant. By immunoprecipitation with polyclonal antibodies raised against Slt2 protein expressed in Escherichia coli, it was possible to confirm that alteration of the lysine-54 residue did not affect the stability of the protein, thus allowing us to conclude that activity of the Slt2 protein kinase is critically required for growth and morphogenesis of S. cerevisiae at 37 degrees C. A significant fraction of the mutant cell population lysed at 24 degrees C and the cells displayed a characteristic alteration of the surface consisting of a typical depression in an area of the cell wall. At 37 degrees C, the cell surface was clearly disorganized.
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PMID:Activity of the yeast MAP kinase homologue Slt2 is critically required for cell integrity at 37 degrees C. 823 2

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

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


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