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)

Halothane, an anesthetic with marked depressant effects on the circulation, was studied for its ability to inhibit inositol phosphate and Ca2+ signaling evoked by the vasoactive hormone arginine vasopressin (AVP) and Ca2+ responses elicited by platelet-derived growth factor and by thapsigargin in cultured A7r5 vascular smooth muscle cells. Changes in apparent [Ca2+]i were measured using the indicator indo-1 and flow cytometry, whereas inositol phosphate levels were determined using myo-[3H]inositol and column chromatography. Preincubation with clinically relevant concentrations of halothane resulted in dose-dependent depression of [Ca2+]i responses evoked on stimulation with AVP. Halothane (2.0%) inhibited the increases in [Ca2+]i by 34-45%. In cells incubated in Ca(2+)-free medium plus 0.5 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, the halothane effect was more marked, with 1.5% halothane inhibiting the responses by approximately 53-61%. However, when Ca2+ influx was stimulated by addition of 5 mM Ca2+ in the continued presence of the agonist, the [Ca2+]i response was inhibited by only 15%, suggesting that release of Ca2+ rather than Ca2+ influx is more sensitive to inhibition by the anesthetic. The effects of halothane on Ca2+ homeostasis are not explained solely by anesthetic-induced depletion of Ca2+ from intracellular stores, because the anesthetic inhibited increases in [Ca2+]i elicited by thapsigargin in cells suspended in Ca(2+)-free medium by only 31%. Halothane inhibited inositol phosphate formation elicited by AVP, suggesting an additional means by which the anesthetic may alter agonist-induced Ca2+ responses. The current results also demonstrate that halothane actions are not specific solely to responses evoked by AVP, which acts via a guanine nucleotide-binding protein-linked signaling pathway, but include responses stimulated by platelet-derived growth factor, an agonist that elevates [Ca2+]i via receptor-latent tyrosine kinase activity. The current results demonstrate that, in vascular smooth muscle cells, halothane alters Ca2+ homeostasis, an action that may underlie the in vivo vasodilator effects of the anesthetic.
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PMID:Halothane inhibits agonist-induced inositol phosphate and Ca2+ signaling in A7r5 cultured vascular smooth muscle cells. 183 33

We established many immunoglobulin-null immature B cell lines transformed by tsOS-59, a temperature-sensitive mutant of Abelson murine leukemia virus. In different cell lines cell growth was depressed and cell differentiation (generation of intracytoplasmic mu-positive cells from Ig- cells) was induced by the shift of culture temperature from low (35 degrees C) to high (39 degrees C). Cell lines were categorized into four groups: (i) temperature sensitive (ts) to both cell growth and differentiation, (ii) ts to cell growth but not to cell differentiation, (iii) ts to cell differentiation but not to cell growth, and (iv) ts to neither cell growth nor differentiation. These results indicated that the depression of cell growth did not necessarily induce cell differentiation, and that cell differentiation was induced regardless of whether cell growth was depressed or not. Furthermore, the results showed that the depression of cell growth and the induction of cell differentiation occurred without the reduction of tyrosine kinase activity of P120gag-abl at high, nonpermissive temperature. Our cell growth and differentiation system described here should provide us with the interesting findings of the relation between B cell growth and differentiation.
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PMID:Unlinked regulation of cell growth and differentiation in immature B cell lines. 211 32

The effect of tumor-promoting phorbol diesters to potentiate the action of epidermal growth factor (EGF) on cell proliferation is associated with phosphorylation of EGF receptors, acute depression of EGF binding, and inhibition of EGF receptor tyrosine kinase activity. In the present studies, normal human fibroblasts and A431 carcinoma cells were labeled with [32P]phosphate and treated with and without 10 nM 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). The EGF receptors then were isolated by immunoprecipitation and digested with trypsin. Analysis of the labeled receptor phosphopeptides by reversed-phase HPLC revealed that PMA induces the phosphorylation of a unique phosphopeptide containing [32P]phosphothreonine. Comparison of several chemical and physical properties of the 32P-labeled phosphopeptide with the primary structure of the EGF receptor suggested the identify Lys-Arg-Thr(P)-Leu-Arg. This was confirmed by direct demonstration that a synthetic peptide of this structure comigrates during HPLC and electrophoresis with the 32P-labeled phosphopeptide isolated from the EGF receptors of normal human fibroblasts. The phosphorylated site on the peptide corresponds to threonine-654 of the EGF receptor, which is located on the cytoplasmic side of the plasma membrane nine residues distant from the transmembrane domain. These data indicate that phosphorylation of the EGF receptor in human fibroblasts and A431 cells at threonine-654 may regulate the EGF receptor tyrosine kinase activity and the binding of EGF.
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PMID:Tumor-promoting phorbol diesters cause the phosphorylation of epidermal growth factor receptors in normal human fibroblasts at threonine-654. 298 76

Levels of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and the tyrosine kinase receptors trkB and trkC have been studied using in situ hybridization in the rat brain after topical application of KCl to the cortical surface (which induces spreading depression). Repeated episodes of spreading depression during 2 h caused a rapid and marked increase of BDNF mRNA levels in deep and, in particular, superficial cortical layers of the ipsilateral hemisphere (to 213 and 417% of control, respectively). Maximal levels were reached within 2 h after the cessation of spreading depression and at 24 h BDNF mRNA expression had returned to control values. Levels of BDNF mRNA were unaffected in the hippocampus, in areas outside the cerebral cortex and in the contralateral hemisphere. Furthermore, no change of the expression of mRNA for NGF, NT-3, trkC or the full length trkB receptor was detected at any time point. However, at 2 h after spreading depression there was an increased level (150% of control) in superficial cortical layers of mRNA hybridizing to an oligonucleotide probe detecting both truncated receptors lacking the tyrosine kinase domain and full length trkB receptors. Also one single episode of spreading depression gave rise to a significant increase of cortical BDNF mRNA levels (to 207% of control), which was attenuated (by 61%) after administration of the competitive NMDA receptor antagonist CGS 19755. The results provide evidence that mild brain insults associated with glutamate release and elevated intracellular calcium, such as spreading depression, also in the absence of seizure activity can lead to activation of the BDNF gene in cortical neurons.
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PMID:Rapid increase of BDNF mRNA levels in cortical neurons following spreading depression: regulation by glutamatergic mechanisms independent of seizure activity. 823 31

Neurotrophic effects resulting from the insulin/insulin receptor system have been recognized as important in determining the etiological basis of neurodegenerative disorders. In Parkinson's disease, selective neuronal loss in the substantia nigra is accompanied by decreased immunoreactivity of the insulin receptor as determined using immunohistochemical studies. We performed semiquantitative mRNA analysis by reverse transcription-polymerase chain reaction (RT-PCR) using specific primers for human insulin receptor exon 22, which encodes a region of the beta subunit of the receptor serving as a tyrosine kinase domain. The relative levels of mRNA in the substantia nigra from Parkinson's brain tissues showed a marked depression compared with those of normal controls. Further investigations are needed to decide whether this is a primary, disease-specific alteration of gene expression or merely a secondary process.
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PMID:Insulin receptor mRNA in the substantia nigra in Parkinson's disease. 893 65

Hypoxia and reoxygenation are principal components of myocardial ischemia and reperfusion and have distinctive effects on the tissue. Both conditions have been associated with inflammation, necrosis, apoptosis, and myocardial infarction. Using a cell culture model of ischemia and reperfusion in which cardiac myocytes were exposed to cycles of hypoxia and reoxygenation, we report here that reoxygenation, but not hypoxia alone, caused sustained approximately 10-fold increases in phosphorylation of the amino-terminal domain of the c-jun transcription factor. The activation was similar to treatments with anisomycin or okadaic acid and correlated with the hypoxia-mediated depression of intracellular glutathione. Reoxygenation-induced c-Jun kinase activity was reduced by preincubating myocytes during the hypoxia phase with the spin-trap agent alpha-phenyl N-tert-butylnitrone or with N-acetylcysteine. The kinase activation was also inhibited by the tyrosine kinase inhibitor genistein but not by other protein kinase inhibitors. These results implicate unquenched reactive oxygen intermediates as the stimulus that initiates a kinase pathway involving the stress-activated protein kinases (JNKs/SAPKs) in reoxygenated cardiac myocytes.
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PMID:Hypoxia/reoxygenation stimulates Jun kinase activity through redox signaling in cardiac myocytes. 904 53

Effects of brain-derived neurotrophic factor (BDNF) in area CA3, the dentate gyrus, and medial entorhinal cortex were examined electrophysiologically by bath application of BDNF in slices containing the hippocampus and entorhinal cortex. Bath application of 25-100 ng/ml BDNF for 30-90 min increased responses to single afferent stimuli in selective pathways in the majority of slices. In area CA3, responses to mossy fiber stimulation increased in 73% of slices and entorhinal cortex responses to white matter stimulation increased in 64% of slices. After exposure to BDNF, these areas also demonstrated evidence of hyperexcitability, because responses to repetitive stimulation (1-Hz paired pulses for several s) produced multiple population spikes in response to mossy fiber stimulation in CA3 or multiple field potentials in response to white matter stimulation in the entorhinal cortex. Repetitive field potentials persisted after repetitive stimulation ended and usually were followed by spreading depression. Enhancement of responses to single stimuli and hyperexcitability were never evoked in untreated slices or after bath application of boiled BDNF or cytochrome C. The tyrosine kinase antagonist K252a (2 microM) blocked the effects of BDNF. In area CA3, both the potentiation of responses to single stimuli and hyperexcitability showed afferent specificity, because responses to mossy fiber stimulation were affected but responses to fimbria or Schaffer collateral stimulation were not. In addition, regional specificity was demonstrated in that the dentate gyrus was much less affected. The effects of BDNF in area CA3 were similar to those produced by bath application of low doses of kainic acid, which is thought to modulate glutamate release from mossy fiber terminals by a presynaptic action. These results suggest that BDNF has acute effects on excitability in different areas of the hippocampal-entorhinal circuit. These effects appear to be greatest in areas that are highly immunoreactive for BDNF, such as the mossy fibers and the entorhinal cortex. Although the present experiments do not elucidate mechanism(s) definitively, the afferent specificity, similarity to the effects of kainic acid, and block by K252a are consistent with previous hypotheses that BDNF affects acute excitability by a presynaptic action on trkB receptors that modulate excitatory amino acid transmission. However, we cannot rule out actions on inhibitory synapses or postsynaptic processes.
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PMID:Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. 930 36

The phosphorylation of proteins on tyrosine residues, initially believed to be primarily involved in cell growth and differentiation, is now recognized as having a critical role in regulating the function of mature cells. The brain exhibits one of the highest levels of tyrosine kinase activity in the adult animal and the synaptic region is particularly rich in tyrosine kinases and tyrosine phosphorylated proteins. Recent studies have described the effects of tyrosine phosphorylation on the activities of a number of proteins which are potentially involved in the regulation of synaptic function. Furthermore, it is becoming apparent that tyrosine phosphorylation is involved in the modification of synaptic activity, such as occurs during depolarization, the induction of long-term potentiation or long-term depression, and ischemia. Changes in the activities of tyrosine kinases and/or protein tyrosine phosphatases which are associated with synaptic structures may result in altered tyrosine phosphorylation of proteins located at the synapse leading to both short-term and long-lasting changes in synaptic and neuronal function.
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PMID:Protein tyrosine phosphorylation: implications for synaptic function. 936 50

We studied the effects of the tyrosine kinase inhibitors genistein and tyrphostin and the tyrosine phosphatase inhibitors sodium orthovanadate and phenylarsine oxide on endotoxin-mediated induction of nitric oxide (NO) synthase in rat aorta and its effects on vascular contractility. Genistein (i.p. 10 mg/kg) inhibited the ex vivo vascular hyporesponsiveness to noradrenaline and the aminoguanidine-sensitive nitrite accumulation induced by endotoxin (i.p. 5 mg/kg) in aortic rings. Low concentrations of genistein (10(-6) M) and tyrphostin (3 x 10(-6) M) inhibited both endotoxin-induced hyporesponsiveness and nitrite and NOx accumulation in vitro in rat aorta without affecting control nitrite or NOx accumulation or contraction. Higher concentrations of genistein (10(-5) and 5.5 x 10(-5) M), sodium orthovanadate (10(-4) M) and phenylarsine oxide (10(-6) M) produced an irreversible depression of noradrenaline-induced contractions. In the presence of these drugs, endotoxin did not induce further depression of vascular contractility and did not increase nitrite or NOx production. In conclusion, there is a dissociation between the effects of these drugs on vascular smooth muscle contraction and NO synthase induction, the latter being more sensitive to inhibition by these drugs. Surprisingly, tyrosine phosphatase inhibitors produced similar effects to those of tyrosine kinase inhibitors, suggesting that there is a complex relationship between tyrosine kinases and phosphatases in the signalling pathway of agonist-induced vascular smooth muscle contraction and NO synthase induction.
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PMID:Effect of tyrosine kinase and tyrosine phosphatase inhibitors on aortic contraction and induction of nitric oxide synthase. 940

We studied synaptic transmission in the granule cells in the olfactory bulb of the homozygous Fyn (a nonreceptor type tyrosine kinase)-deficient (fynz/fynz) and heterozygous Fyn-deficient (+/fynz) mice by using slice preparations from the olfactory bulb. Stimulation to the lateral olfactory tract and/or centrifugal fibers to the olfactory bulb evoked field excitatory postsynaptic potentials (fEPSPs) in the granule cells. In +/fynz mice, fEPSPs were augmented by bicuculline, a gamma-aminobutyric acid (GABAA) antagonist and picrotoxin, whereas fEPSPs in fynz/fynz mice were much less sensitive to bicuculline and picrotoxin. Application of D-2-amino-5-phosphonopentanoic acid had no effect but 6-cyano-7-nitroquinoxaline-2,3-dione produced almost complete block of fEPSPs in both +/fynz mice and fynz/fynz mice. (1S,3R)-1-aminocyclo-pentane-1.3-dicarboxylate, an agonist of metabotropic glutamate receptors caused a similar depression of fEPSPs in both +/fynz and fynz/fynz mice. In +/fynz mice tetanic stimulation to the lateral olfactory tract and/or centrifugal fibers induced N-methyl-D-aspartate (NMDA)-dependent long-term potentiation (LTP) of fEPSPs, whereas LTP was impaired in fynz/fynz mice. Our results demonstrate altered functions of GABAA and NMDA receptors in the olfactory system of Fyn-deficient mice.
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PMID:Abnormal synaptic transmission in the olfactory bulb of Fyn-kinase-deficient mice. 942 84


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