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  • 1
    Electronic Resource
    Electronic Resource
    A Role for Amplified Protein Kinase C Activity in the Pathogenesis of Amyotrophic Lateral Sclerosis (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 65 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Amyotrophic lateral sclerosis (ALS) is a human neurodegenerative disorder of unknown origin that is characterized by progressive degeneration of corticospinal tracts and anterior horn cells in the brainstem and spinal cord. Previous studies have indicated that motoneuron degeneration associated with ALS may be triggered by mechanisms leading to increased intracellular Ca2+. In the present report, Ca2+-activated phospholipid-dependent protein kinase C (PKC) was evaluated in cervical spinal cords from ALS patients and control subjects. In patients who died with ALS, PKC histone H1 phosphotransferase activity was significantly increased by 330% in cytosolic- and 118% in particulate-derived extracts compared with controls. This increase in PKC phosphotransferase activity appeared to be partially due to an increase in the amount of PKC protein present in ALS spinal cord tissue. PKC histone H1 phosphotransferase activities of cytosolic- and particulate-derived extracts from motor and visual cortex of ALS patients and controls were not statistically different, nor were there differences in PKC histone H1 phosphotransferase activity in platelets and leukocytes. The specific nature of PKC alterations in affected regions of the CNS supports a role for PKC in the events leading to motoneuron death in sporadic ALS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.65020927.x
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  • 2
    Electronic Resource
    Electronic Resource
    Activation of p42 Mitogen-Activated Protein Kinase by Glutamate Receptor Stimulation in Rat Primary Cortical Cultures (1993)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 61 (1993), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— Recent studies have identified at least two homologous mitogen-activated protein (MAP) kinases that are activated by phosphorylation of both tyrosine and threonine residues by an activator kinase. To help define the role of these MAP kinases in neuronal signalling, we have used primary cultures derived from fetal rat cortex to assess the regulation of their activity by agonist stimulation of glutamate receptors and by synaptic activity. Regulation was assayed by monitoring changes in both tyrosine phosphorylation on western blots and in vitro kinase activity toward a selective MAP kinase substrate peptide. In initial studies, we found that phorbol ester treatment increased tyrosine phosphorylation of p42 MAP kinase and stimulated MAP kinase activity. A similar response was elicited by three agonists of metabotropic glutamate receptors, i.e., trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid, quisqualate, and (2S,3S,4S)-α-(carboxycyclopropyl)glycine. MAP kinase activity and p42 MAP kinase tyrosine phosphorylation were also stimulated by the ionotropic glutamate receptor agonist, kainate, but not by N-methyl-d-aspartate. To examine regulation of MAP kinase by synaptic activity, cultures were treated with picrotoxin, an inhibitor of GABAA receptor-mediated inhibition that enhances spontaneous excitatory synaptic activity. Treatment of cultures with picrotoxin elicited activation of MAP kinase. This response was blocked by tetrodotoxin, which suppresses synaptic activity. These results demonstrate that p42 MAP kinase is activated by glutamate receptor agonist stimulation and by endogenous synaptic activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1993.tb09796.x
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  • 3
    Electronic Resource
    Electronic Resource
    Modulation of NMDA-mediated excitotoxicity by protein kinase C (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 78 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Excessive activation of N-methyl-d-aspartate (NMDA) receptors leads to cell death in human embryonic kidney-293 (HEK) cells which have been transfected with recombinant NMDA receptors. To evaluate the role of protein kinase C (PKC) activation in NMDA-mediated toxicity, we have analyzed the survival of transfected HEK cells using trypan blue exclusion. We found that NMDA-mediated death of HEK cells transfected with NR1/NR2A subunits was increased by exposure to phorbol esters and reduced by inhibitors of PKC activation, or PKC down-regulation. The region of NR2A that provides the PKC-induced enhancement of cell death was localized to a discrete segment of the C-terminus. Use of isoform-specific PKC inhibitors showed that Ca2+- and lipid-dependent PKC isoforms (cPKCs), specifically PKCβ1, was responsible for the increase in cell death when phorbol esters were applied prior to NMDA in these cells. PKC activity measured by an in vitro kinase assay was also increased in NR1A/NR2A-transfected HEK cells following NMDA stimulation. These results suggest that PKC acts on the C-terminus of NR2A to accentuate cell death in NR1/NR2A-transfected cells and demonstrate that this effect is mediated by cPKC isoforms. These data indicate that elevation of cellular PKC activity can increase neurotoxicity mediated by NMDA receptor activation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00459.x
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  • 4
    Electronic Resource
    Electronic Resource
    Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 85 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The Kinetworks™ multi-immunoblotting technique was used to evaluate the expressions of 78 protein kinases, 24 protein phosphatases and phosphorylation states of 31 phosphoproteins in thoracic spinal cord tissue from control subjects and patients having the sporadic form of amyotrophic lateral sclerosis (ALS). In both the cytosolic (C) and particulate (P) fractions of spinal cord from ALS patients as compared with controls, there were increased levels of calcium/calmodulin-dependent protein kinase kinase (CaMKK; C = 120% increase/P = 580% increase;% change, compared with control), extracellular regulated kinase 2 (ERK2; C = 120% increase/P = 170% increase), G protein-coupled receptor kinase 2 (GRK2; C = 140% increase/P = 140% increase), phospho-Y279/216 glycogen synthase kinase 3 α/β (GSK3α/β; C = 90% increase/P = 220% increase), protein kinase B α (PKBα; C = 360% increase/P = 200% increase), phospho-T638 PKCα/β (C = 630% increase/P = 170% increase), cGMP-dependent protein kinase (PKG; C = 100% increase/P = 75% increase), phospho-T451 dsRNA-dependent protein kinase (PKR; C = 2600% increase/P = 3330% increase), ribosomal S6 kinase 1 (RSK1; C = 750% increase/P = 630% increase), phospho-T389 p70 S6 kinase (S6K; C = 1000% increase/P = 460% increase), and protein-tyrosine phosphatase 1 δ (PTP1δ; C = 43% increase/P = 70% increase). Cytosolic increases in phospho-α-S724/γ-S662 adducin (C = 15650% increase), PKCα (C = 100% increase) and PKCζ (C = 190% increase) were found in ALS patients as compared with controls, while particulate increases in cAMP-dependent protein kinase (PKA; 43% increase), protein kinase C β (PKCβ; 330% increase), and stress-activated protein kinase β (SAPKβ; 34% increase) were also observed. Cyclin-dependent kinase-associated phosphatase (KAP) was apparently translocated, as it was reduced (31% decrease) in cytosolic fractions but elevated (100% increase) in particulate fractions of ALS spinal cord tissue. Our observations indicate that ALS is associated with the elevated expression and/or activation of many protein kinases, including PKCα, PKCβ, PKCζ and GSK3α/β, which may augment neural death in ALS, and CaMKK, PKBα, Rsk1, S6K, and SAPK, which may be a response to neuronal injury that potentially can mitigate cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01670.x
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  • 5
    Electronic Resource
    Electronic Resource
    Isolation of various forms of sterol β-d-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 82 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol β-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin–dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00976.x
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  • 6
    Electronic Resource
    Electronic Resource
    Phosphatidylinositol 3-Kinase: Increased Activity and Protein Level in Amyotrophic Lateral Sclerosis (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Enzyme activities and protein levels of several protein and lipid kinases were measured in postmortem tissue from patients who died with amyotrophic lateral sclerosis (ALS) as well as from control subjects. Patients who died with ALS had increased activities and protein levels of phosphatidylinositol 3-kinase (PI 3-K) in particulate fractions of spinal cord tissue compared with control subjects. The PI 3-K activity increased with PI 3-K protein level, indicating no change in specific PI 3-K activity in ALS. No differences in PI 3-K activities were found in cytosolic fractions of spinal cord, or in motor and visual cortices, from ALS patients compared with those from controls. PI 3-K activities and protein levels were unchanged in brain tissue from patients who died with Alzheimer's disease compared with those from controls. PI 3-K is a lipid kinase that is important for cell survival and is activated in response to many growth factors. Increased PI 3-K activities in particulate fractions of spinal cord from ALS patients may be related to the increase of PI 3-K protein levels found in this tissue. The protein kinases Erk2, protein kinase B (PKB), and p70 ribosomal S6 kinase (S6K) showed no differences in activities in spinal cord tissue between ALS patients and controls. However, the amounts of PKB and S6K protein were significantly higher in ALS patients, whereas Erk2 protein amount was unchanged compared with controls. Protein kinase C activity was increased in spinal cord tissue from ALS patients, which is consistent with our previous report. The increased activity of PI 3-K in spinal cord tissue from patients with ALS implicates the involvement or activation of PI 3-K in ALS, as either a cause or a consequence of the neuron loss. The lack of up-regulation in the activities of PKB and S6K in ALS tissue supports an impairment in signal transduction cascades mediated by PI 3-K in this neurodegenerative disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71020716.x
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  • 7
    Electronic Resource
    Electronic Resource
    Reduction of angiotensin II-induced activation of mitogen-activated protein kinase in cardiac hypertrophy (1997)
    Springer
    Cellular and molecular life sciences 53 (1997), S. 951-959 
    Details
    ISSN: 1420-9071
    Keywords: Key words. Mitogen-activated protein (MAP) kinase; cardiac hypertrophy; Dahl rat; angiotensin II.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Mitogen-activated protein (MAP) kinases play a role in cell growth and are activated in the heart by cardiac stretch and various growth factors, but their role in signal transduction pathways once the heart has undergone hypertrophy is uncertain. To investigate the regulation of MAP kinases in the heart in response to angiotensin II (ang II), once cardiac hypertrophy has become established, ventricular and skeletal muscle explants were studied from Dahl S salt-sensitive and Dahl R salt-resistant rats that were on a high (6% NaCl) salt supplement in their diet. Cardiac hypertrophy was produced in the Dahl S but not R rat through NaCl-induced hypertension. MAP kinases were assayed by myelin protein phosphotransferase activity in MonoQ fractions of cell extracts. Ang II increased MAP kinases mainly in extracts from nonhypertrophic ventricles of Dahl R rats on a high-salt diet. Immunoblots revealed predominantly p44ERK1 with lower amounts p42MAPK in rat ventricle, and no apparent changes with hypertrophy. In hypertrophied hearts, ang II-induced MAP kinase activity was less markedly increased and more rapdily fell to baseline levels in comparison to the response in nonhypertrophied hearts. Prolonged ang II exposure did not produce the same effect on MAP kinase activity in ventricles from Dahl S rats on a low-salt diet, or skeletal muscle from salt-fed Dahl R and S rats. The ability of phorbol myristate acetate to simulate MAP kinase and ang II to simulate translocation of protein kinase C from the cytosole to the membrane was similarly compromised in hypertrophied ventricles. These results are consistent with a disturbance in the regulation of cell-signalling pathways in cardiac hypertrophy in which the MAP kinase response to ang II is dramatically altered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s000180050116
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