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)

The induction of synaptic plasticity is known to be influenced by the previous history of the synapse, a process termed metaplasticity. Here we demonstrate a novel metaplasticity in which group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of synaptic transmission is regulated by previous mGluR activation. In these studies, the group I mGluR-dependent LTD induced by the selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD) was inhibited by previous preconditioning brief high-frequency stimulation (HFS), regardless of whether the preconditioning HFS induced long-term potentiation. Blockade of NMDA receptors during the preconditioning HFS did not alter the inhibition of DHPG-LTD by the HFS. However, antagonism of mGluRs during the preconditioning HFS did prevent the inhibition of DHPG-LTD by the HFS. In addition, blocking PKC stimulation during the preconditioning HFS also prevented the inhibitory effect of HFS on DHPG-LTD. The DHPG-LTD itself was not inhibited by blocking PKC stimulation but was inhibited by blocking the p38 mitogen-activated protein kinase (MAPK) pathway. Thus, whereas the DHPG-LTD is mediated via activation of the p38 MAPK pathway, the inhibitory effects of preconditioning HFS on DHPG-LTD are mediated via stimulation of group I/II mGluRs, activation of PKC, and subsequent blocking of the functioning of group I mGluR.
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PMID:Group I metabotropic glutamate receptor (mGluR)-dependent long-term depression mediated via p38 mitogen-activated protein kinase is inhibited by previous high-frequency stimulation and activation of mGluRs and protein kinase C in the rat dentate gyrus in vitro. 1212 73

Recent evidence has emphasized the importance of p38 mitogen-activated protein kinase (MAPK) in the induction of metabotropic glutamate receptor (mGluR)-dependent long term depression (LTD) at hippocampal CA3-CA1 synapses. However, the cascade responsible of mGluR to activate p38 MAPK and the signaling pathway immediately downstream from it to induce synaptic depression is poorly understood. Here, we show that transient activation of group I mGluR with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) activates p38 MAPK through G protein betagamma-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD. Furthermore, our data clearly show that an accelerating AMPA receptor endocytosis by stimulating the formation of guanyl nucleotide dissociation inhibitor-Rab5 complex is a potential downstream processing of p38 MAPK activation to mediate DHPG-LTD. These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors.
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PMID:Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. 1470 49

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.
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PMID:Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. 1536 93

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.
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PMID:Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury. 1576 71

Previous studies have shown that brief application of group I metabotropic glutamate receptor (mGluR) agonist (S)-3, 5-dihydroxyphenylglycine (DHPG) to hippocampal slices can induce a chemical form of long-term depression (DHPG-LTD) in the hippocampal CA1 region; however, the expression mechanisms of this LTD remain unclear. We show here that the expression of DHPG-LTD can be specifically reversed by application of the broad-spectrum mGluR antagonists, (S)-alpha-methyl-4-carboxyphenylglycine (MCPG) and LY341495, and mGluR5 antagonist, 2-methyl-6-(phenylethyl)pyridine, but not by NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid, mGluR1 antagonist, LY367385, group II mGluR antagonist, (2S)-alpha-ethylglutamic acid, or group III mGluR antagonist, (S)-2-amino-2-methyl-4-phosphonobutanic acid (MAP4). In addition, the ability of MCPG to reverse DHPG-LTD was mimicked by the protein tyrosine phosphatase inhibitors, phenylarsine oxide and orthovanadate, but not phospholipase C inhibitor, U73122, protein kinase C inhibitor, bisindolylmaleimide 1, p38 mitogen-activated protein kinase inhibitor, SB203580, or protein phosphatases 1/2 A inhibitor, okadaic acid. Moreover, MCPG reversed the DHPG-LTD without affecting the paired-pulse facilitation. The expression of DHPG-LTD was associated with the reduction of both tyrosine phosphorylation and surface expression of AMPA receptor GluR2 subunits. Together, these results suggest that sustained activation of mGluR5 and in turn triggering a protein tyrosine phosphatase-dependent regulation of postsynaptic expression of AMPA receptors may contribute to the expression of DHPG-LTD.
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PMID:Sustained activation of metabotropic glutamate receptor 5 and protein tyrosine phosphatases mediate the expression of (S)-3,5-dihydroxyphenylglycine-induced long-term depression in the hippocampal CA1 region. 1627 5

Respiratory dysfunction during sepsis is common. However, although lung function can often be adequately supported, death frequently results from cardiovascular collapse. Despite intense investigation, the mechanism underlying the myocardial dysfunction of sepsis remains unclear. Macrophage migration inhibitory factor (MIF), an important cytokine released in sepsis and the acute respiratory distress syndrome, is a known cardiac depressant. We hypothesized that MIF released from the lung results in myocardial dysfunction during sepsis. In murine models of polymicrobial sepsis, we demonstrate a significant increase in the lungs of total and lavagable MIF between 20 and 30 h post induction of sepsis. At 30 h post sepsis, the lungs released MIF into the pulmonary circulation, increasing the plasma concentration by up to 51% in a single pass. Exogenous MIF, instilled into the lungs, increased alveolar keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-2 (MIP2), and tumor necrosis factor alpha (TNFalpha) at 3 h, and plasma KC and MIP2 at 6 h postinstillation. This was associated with an increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. Because changes in mitogen-activated protein kinase activation can lead to myocardial depression, these data suggest that MIF released from the lungs may be responsible, at least in part, for the cardiac dysfunction seen in the late stages of sepsis.
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PMID:Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis. 1631 87

Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.
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PMID:n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. 2894 69

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1 receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1 receptor activation [with N6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1 receptors. Phospho-p38 MAPK activation by A1 receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1 receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 microM), the A1 receptor agonist CPA (40 nM), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1 receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nM) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 microM) blocked the inhibitory actions of A1 receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4'-pyridyl)-1H-imidazole] (25 microM) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2'-amino-3'-methoxyflavone] (50 microM) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABA(B)-mediated synaptic depression. These data suggest A1 receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3-CA1 synaptic transmission.
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PMID:p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. 1713 4

The present study aimed to determine the thermal response of the Mediterranean mussel Mytilus galloprovincialis by integrating information from various levels of biological organization including behavior, metabolic adjustments, heat shock protein expression, and protein kinase activity. Behavioral responses were determined by examining the effect of warming on valve closure and opening. Metabolic impacts were assessed by examining the activity of the key glycolytic enzyme pyruvate kinase (PK). Molecular responses were addressed through the expression of Hsp70 and Hsp90 and the phosphorylation of stress-activated protein kinases, p38 mitogen-activated protein kinase (p38 MAPK) and cJun-N-terminal kinases (JNKs). Mussels increased the duration of valve closure by about sixfold when acclimated to 24 degrees C rather than to 17 degrees C. As indicated by the activity of PK, such behavior caused metabolic depression and probably a shift from aerobic to anaerobic metabolism. Acclimation to temperatures higher than 24 degrees C caused an increase in mortality and induced the expression of Hsp72. Increased phosphorylation of p38 MAPK and JNKs indicated activation of MAPK signaling cascades. The potential involvement of MAPKs in the induction of Hsp genes in the tissues of M. galloprovincialis is discussed. In conclusion, it seems that M. galloprovincialis lives close to its acclimation limits and incipient lethal temperature and that a small degree of warming will elicit stress responses at whole organism and molecular levels.
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PMID:Behavioral, metabolic, and molecular stress responses of marine bivalve Mytilus galloprovincialis during long-term acclimation at increasing ambient temperature. 1752 22

The p38 mitogen-activated protein kinase (MAPK) and activated MAPK transcription factors c-jun, c-myc, and elk-1 were investigated in rat enterocytes after sublethal poisoning with soman to study the pathogenetic mechanism of nonspecific long-term effects of nerve agents. Wistar rats were poisoned by intramuscular administration of soman at a dose 60 microg x kg(-1) (70% LD(50)) and sacrificed by cervical dislocation 3 and 5 days after poisoning. Control groups were administered physiologic saline instead of soman. Protein expression in immunohistochemically stained samples from colon transversum of control and poisoned rats was measured using image analysis. In comparison with control groups, activated p38 MAPK from soman-poisoned rats was significantly depressed at both time intervals. c-myc and c-jun expression was significantly increased 3 days after soman poisoning. On the other hand, a decrease in c-myc and c-jun expression was observed 5 days after soman poisoning. No changes in elk-1 expression were found. Long-term depression of MAPK pathway members might allow cells to proliferate in poisoned rats. This mechanism can be linked with apoptosis and carcinogenesis.
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PMID:Alteration of mitogen-activated protein kinase pathway after soman poisoning. 1761 12


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