Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed immune disturbances caused by the influence of spaceflight factors and proposed approaches for their correction. First, we determined the significant resistance of humoral immunity to the action of spaceflight factors, for example, B cell and immunoglobulin content, B cell reactivity to lipopolysaccharide, and distribution of B cell clones to trinitrophenyl (TNP group). A brief reversible increase of IgA and/or IgG concentration was the most characteristic shift observed. However, we noted prominent changes of T cells and natural killer (NK) cells, such as decreases in the content and phytohemagglutinin (PHA) reactivity of T lymphocytes, reduced T helper activity, and a reduction in NK cell cytotoxic activity in humans and animals during prolonged, spaceflights. Rat bone marrow cells showed a decreased response to macrophage colony-stimulating factor. Studies with rat lymph node cells showed that microgravity and spaceflight stressors may influence lymphocytes in a tissue-specific manner. In experiments on isolated cells, human lymphocytes produced interferon more intensively in a reduced-gravity (microgravity) environment than under terrestrial conditions. However, lymphocyte activation by concanavalin A was sharply suppressed. Under microgravity conditions the transfer of activating signal to protein kinase C was strongly reduced. Thus, in-flight disturbances of T and NK cell functions are quite significant and could cause some diseases. However, to date the in-flight immune dysfunctions have not been excessive. Probably, we are mainly dealing with a complex of changes of immunity in space that is similar to that in the presence of acute stress. Therefore, it is reasonable to consider stress-related immunotherapy approaches in the practice of space medicine. The most effective methods and approaches of modern immunotherapy, such as artificial vaccines, monoclonal antibodies and immunoconjugates, recombinant cytokines, or immunomodulators etc, are also reviewed.
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PMID:Countermeasures for ameliorating in-flight immune dysfunction. 837 Oct 54

The long-term consequences of acute stress on [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, a marker for protein kinase C (PKC) activity, were investigated. In the first experiment, exposure to acute restraint and intermittent tail-shock increased [3H]PDBu binding in the amygdala but not in the hippocampus or cerebral cortex. The increase was persistent, lasting at least 24 h after stressor cessation. In the second experiment, it was determined that the stress-induced increase in binding in the amygdala was dependent on NMDA receptor activation; rats injected with a competitive NMDA receptor antagonist prior to the stressor did not exhibit the increased binding in the amygdala 24 h later. In the third experiment, re-exposure to the stressful context 96 h after stressor cessation reactivated the stress-induced increase the binding of [3H]PDBu in the amygdala. Re-exposure to the context also increased binding in the thalamus and area CA1 of the hippocampus. [3H]PDBu binds preferentially to PKC in the membrane and, therefore, these results suggest that stress induces the translocation of PKC from its resting compartments in the cytosol to the membrane. Its dependence on NMDA receptor activation implicates isoforms of PKC that are sensitive to intracellular calcium, such as PKC gamma. The results further suggest that a "psychological' manipulation, viz. context re-exposure, can reactivate the persistent increase in [3H]PDBu binding in the amygdala.
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PMID:Stress persistently increases NMDA receptor-mediated binding of [3H]PDBu (a marker for protein kinase C) in the amygdala, and re-exposure to the stressful context reactivates the increase. 909 55

At least two hypothalamic peptides, corticotropin releasing hormone (CRH) and vasopressin (VP), are important in regulating adrenocorticotropin (ACTH) release from the anterior pituitary. Both are secreted in a pulsatile manner and stimulate ACTH secretion by interacting with G protein-coupled receptors (GPCRs), namely the type 1 CRH receptor and V1b receptor, respectively. Repeated or prolonged stimulation with either peptide can cause reduced ACTH responsiveness or desensitisation, both in vivo and in vitro. Desensitisation of perifused sheep anterior pituitary cells to VP was found to be rapid and occurred following treatment with 5 nM VP for 5 min. This is within the range of concentrations and durations of VP pulses seen in sheep portal blood during acute stress. In contrast, significant desensitisation of the ACTH response to CRH required pre-treatment for longer than 25 min with a CRH concentration of 1 nM, suggesting that endogenous pulses may not elicit desensitisation. Although rapid GPCR desensitisation involves uncoupling of receptors from their G proteins, commonly mediated by receptor phosphorylation, and internalisation of receptors, desensitisation of neither the CRH nor VP receptor was mediated by PKA or PKC, respectively. Desensitisation of the response to VP was found to be dependent upon receptor internalisation, and resensitisation could be delayed by treatment with a protein phosphatase 2B inhibitor. The rapid kinetics of desensitisation of the ACTH response to VP suggest that this process is important in regulating the response to acute rather than chronic stress. If, as has been suggested, CRH acts in a permissive way to set corticotrope gain, desensitisation to CRH could also be important in long term regulation of ACTH secretion.
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PMID:Acute and chronic regulation of pituitary receptors for vasopressin and corticotropin releasing hormone. 1193 3

Hemodialysis patients exhibit a defective immune response leading to an increased susceptibility of infections and neoplasms. Far from being helpful, dialytic therapy per se also may be responsible for this acquired immunodeficiency. Dialysis membranes and bacterial products present in dialysis water may trigger and even perpetuate an abnormal mononuclear cell activation. Upon contact with cellulosic dialysis membranes, monocytes display an increased expression of surface markers of cell activation, such as adhesion molecules CD18, CD49, CD54 and the lipopolysaccharide (LPS) ligand (CD14). Moreover, proinflammatory cytokines as IL-1beta and TNF-alpha are released both in vivo and in vitro when monocytes are exposed to cellulosic membranes. Of special interest is the fact that end-stage renal disease patients undergoing hemodialysis exhibit an increased mononuclear cell apoptosis. This apoptosis is directly related to the degree of biocompatibility of the dialysis membrane. Apoptosis is activated when monocytes enter in contact with the cellulosic dialysis membrane through cell surface receptors linked to G-proteins. In early steps of apoptosis signaling, pertussis toxin-sensitive G proteins are coupled to protein kinase C (PKC)-dependent phosphorylative mechanisms. Furthermore, recent evidence support that the execution phase of apoptosis is mediated by a caspase-3 dependent pathway. Finally, very recent available data support that monocytes subjected to repeated activation suffer a process of accelerated senescence, as demonstrated by the senescent phenotype (CD14 and CD32) expressed and their shortened telomeric length. This senescent profile may generage a defective cellular response in acute stress situations, explaining (at least in part) the altered immune response observed in hemodialysis patients.
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PMID:Cell apoptosis and hemodialysis-induced inflammation. 1198 20

The myristoylated alanine-rich C kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in brain that binds the inner surface of the plasma membrane, calmodulin, and cross-links filamentous actin, all in a PKC phosphorylation-reversible manner. MARCKS has been implicated in hippocampal-dependent learning and long-term potentiation (LTP). Previous studies have shown DBA/2 mice to exhibit poor spatial/contextual learning, impaired hippocampal LTP, and hippocampal mossy fiber hypoplasia, as well as reduced hippocampal PKC activity and expression relative to C57BL/6 mice. In the present study, we assessed the expression (mRNA and protein) and subcellular distribution (membrane and cytolsol) of MARCKS in the hippocampus and frontal cortex of C57BL/6 and DBA/2 mice using quantitative western blotting. In the hippocampus, total MARCKS mRNA and protein levels in C57BL/6J mice were significantly lower ( approximately 45%) compared with DBA/2J mice, and MARCKS protein was observed predominantly in the cytosolic fraction. MARCKS expression in frontal cortex did not differ significantly between strains. To examine the dynamic regulation of MARCKS subcellular distribution, mice from each strain were subjected to 60 min restraint stress and MARCKS subcellular distribution was determined 24 h later. Restraint stress resulted in a significant reduction in membrane MARCKS expression in C57BL/6J hippocampus but not in the DBA/2J hippocampus despite similar stress-induced increases in serum corticosterone. Restraint stress did not affect cytosolic or total MARCKS levels in either strain. Similarly, restraint stress (30 min) in rats also induced a significant reduction in membrane MARCKS, but not total or cytosolic MARCKS, in the hippocampus but not in frontal cortex. In rats, chronic lithium treatment prior to stress exposure reduced hippocampal MARCKS expression but did not affect the stress-induced reduction in membrane MARCKS. Collectively these data demonstrate higher resting levels of MARCKS in the hippocampus of DBA/2J mice compared to C57BL/6J mice, and that acute stress leads to a long-term reduction in membrane MARCKS expression in C57BL/6J mice and rats but not in DBA/2J mice. These strain differences in hippocampal MARCKS expression and subcellular translocation following stress may contribute to the differences in behaviors requiring hippocampal plasticity observed between these strains.
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PMID:Differential expression and regulation of myristoylated alanine-rich C kinase substrate (MARCKS) in the hippocampus of C57/BL6J and DBA/2J mice. 1267 22

The stress-related neuropeptide corticotropin-releasing factor (CRF) and the serotonin system are both critically involved in the pathophysiology of mental disorders, including anxiety and depression. To understand the potential link between them, we investigated the impact of CRF on 5-HT functions in pyramidal neurons of the prefrontal cortex (PFC), a brain region that is crucial for the control of emotion and cognition. One prominent function of serotonin in PFC is to regulate GABAergic inhibitory transmission, as indicated by a 5-HT-induced large, desensitizing (approximately 4 min) enhancement of the amplitude and frequency of spontaneous IPSCs (sIPSCs). In PFC slices exposed to CRF treatment, the regulation of sIPSCs by 5-HT was significantly prolonged (8-10 min), and this effect of CRF was blocked by treatment with the competitive CRF receptor antagonist alpha-helical CRF9-41 and with the CRF-R1-specific antagonist astressin. Inhibiting phospholipase C or protein kinase C (PKC) abolished the prolongation by CRF of the effects of 5-HT on sIPSCs. In PFC slices prepared from animals previously exposed to acute stress (forced swim or elevated platform), the regulation of sIPSCs by 5-HT was significantly prolonged, mimicking the effect of CRF treatment. The stress-induced prolongation of the effects of 5-HT on sIPSCs was diminished by alpha-helical CRF9-41 treatment, mimicked by direct activation of PKC, and reversed by short-term treatment with drugs that have anxiolytic efficacy. These results show that in response to stressful stimuli, CRF alters the serotonergic regulation of GABA transmission through a mechanism that is dependent on PKC. The interaction between CRF and 5-HT may play an important role in psychiatric disorders, in which both are highly implicated.
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PMID:Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. 1516 92

Protein kinase C gamma (PKC gamma) is highly expressed in the rodent hippocampus and has been implicated in long-term alterations in synaptic efficacy. Acute stress has been shown to negatively affect hippocampal synaptic plasticity, and the present study examined the effect of acute stress on PKC gamma expression/subcellular distribution by quantitative western blotting in two inbred mouse strains (C57BL/6J versus DBA/2J) with established differences in hippocampal plasticity. It was found that both DBA/2J and C57BL/6J strains exhibited similar basal, stress-induced elevations, and recovery of serum corticosterone levels. Acute stress produced a significant reduction in both membrane and cytosolic PKC gamma expression in the hippocampus of C57BL/6J mice compared to no-stress controls, but did not alter either membrane or cytosolic PKC gamma expression in the hippocampus of DBA/2J mice compared to no-stress controls. These data provide direct evidence that PKC gamma is differentially regulated in the hippocampus of C57BL/6J and DBA/2J mice by acute stress. The role of stress-induced regulation of hippocampal PKC gamma expression in hippocampal synaptic plasticity is discussed.
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PMID:Acute restraint stress reduces protein kinase C gamma in the hippocampus of C57BL/6 but not DBA/2 mice. 1536 14

Adrenal medullary chromaffin cells release catecholamines and neuropeptides in an activity-dependent manner controlled by the sympathetic nervous system. Under basal sympathetic tone, catecholamines are preferentially secreted. During acute stress, increased sympathetic firing evokes release of both catecholamines as well as neuropeptides. Both signalling molecules are co-packaged in the same large dense core granules, thus release of neuropeptide transmitters must be regulated after granule fusion with the cell surface. Previous work has indicated this may be achieved through a size-exclusion mechanism whereby, under basal sympathetic firing, the catecholamines are selectively released through a restricted fusion pore, while less-soluble neuropeptides are left behind in the dense core. Only under the elevated firing experienced during the sympathetic stress response do the granules fully collapse to expel catecholamines and neuropeptides. However, mechanistic description and physiological regulation of this process remain to be determined. We employ electrochemical amperometry, fluid-phase dye uptake and electrophysiological capacitance noise analysis to probe the fusion intermediate in mouse chromaffin cells under physiological electrical stimulation. We show that basal firing rates result in the selective release of catecholamines through an Omega-form 'kiss and run' fusion event characterized by a narrow fusion pore. Increased firing raises calcium levels and activates protein kinase C, which then promotes fusion pore dilation until full granule collapse occurs. Our results demonstrate that the transition between 'kiss and run' and 'full collapse' exocytosis serves a vital physiological regulation in neuroendocrine chromaffin cells and help effect a proper acute stress response.
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PMID:Physiological stimulation regulates the exocytic mode through calcium activation of protein kinase C in mouse chromaffin cells. 1678 16

Cognitive aspects of the acute stress response are partly mediated through activation of the locus coeruleus (LC)-norepinephrine (NE) system via corticotropin-releasing factor (CRF). Apart from mediating the acute responses to stress, CRF can mediate the long-term impact of stress on the brain through its potent modulation of neuronal morphology. Importantly, the cellular pathways engaged by stress in general, and CRF in particular, in remodeling neuronal structure are poorly understood. Here, we demonstrate that apart from its well-established acute effects on LC neuronal activity, CRF also stimulates growth and arborization of LC neuronal processes. By contrast, urocortin 2 (UCN 2), a related peptide, inhibits outgrowth of such processes. These opposing effects are transduced by a common receptor (CRF(1)) but distinct intracellular signaling pathways. The structural effects of CRF required protein kinase A and mitogen-activated protein kinase, as well as Rac1, a member of the Rho family of GTPases that regulates the actin and microtubule cytoskeleton. By contrast, the effects of UCN II were mediated by the protein kinase C and RhoA pathways. This is the first study to link stress-related substrates to molecular mediators of actin cytoskeletal remodeling in the LC. We propose a model of dynamic LC neuronal plasticity that is reciprocally controlled by CRF and UCN II, eventually determining actin rearrangement by Rho-specific pathways. By regulating the extension of processes into pericoerulear regions where limbic afferents terminate, these peptides may determine the degree to which the LC-NE system is influenced by limbic structures that mediate emotional expression.
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PMID:Corticotropin-releasing factor promotes growth of brain norepinephrine neuronal processes through Rho GTPase regulators of the actin cytoskeleton in rat. 1710 Aug 37

miRNAs (microRNAs) play important roles in diverse physiological processes, including stress response, apoptosis and carcinogenesis. Even though the role of individual miRNAs has been demonstrated, expression of proteins involved in miRNA production in response to acute stress or harmful agents has not been extensively investigated. Here, we have studied the role of Dicer, one of the central proteins of the miRNA processing machinery during apoptosis, and show that down-regulation of Dicer results in accelerated apoptosis of HeLa cells, triggered by TNFalpha (tumour necrosis factor alpha). We have also investigated the integrity of Dicer, and provide evidence that Dicer is a target for caspases during apoptosis. The cleavage of Dicer is stimulidependent and more pronounced when apoptosis is induced by PKC (protein kinase C) inhibitors, and can also be observed in HIV-1-infected cells at late stages of infection. Thus the apoptotic machinery may regulate the miRNA pathway by affecting individual proteins, such as Dicer.
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PMID:Stimuli-dependent cleavage of Dicer during apoptosis. 1828 25


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