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)

The gamma isoform of protein kinase C (gamma-PKC) activity is elevated and learning is superior in the inbred C57BL/6 mouse when compared to the DBA/2 mouse strain. Given the proposed link between PKC and long-term potentiation (LTP) on the one hand and PKC and learning on the other, it was predicted that LTP persistence would be greater in C57BL/6 mouse. When suprathreshold levels of tetanic stimulation were used, similar persistent LTP was observed in both C57BL/6 and DBA/2 strains. However, when tetanus was at threshold, the response in DBA/2 mice decayed to baseline in 30 min, similar to short-term potentiation (STP). Using this same paradigm with C57BL/6 mice, LTP persisted for 4 h, the longest time tested. The time course of the results parallels those observed in rat when phorbol ester, a potent PKC activator, converts STP to LTP. The present findings thus confirm the predicted difference between the two mouse strains. Moreover, the present findings are consistent with a role for gamma-PKC in LTP. Since such results call attention to the need for gamma-PKC interventive procedures, the relative utility of current PKC inhibitors, null mutants and antisense methods are discussed.
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PMID:Long-term potentiation persistence greater in C57BL/6 than DBA/2 mice: predicted on basis of protein kinase C levels and learning performance. 927 37

Ocular surface mucin is secreted from both goblet cells in the conjunctival epithelium and corneal epithelial cells. To clarify its mechanism of secretion in corneal epithelial cells, a rat cornea organ culture system was used to evaluate the second messenger roles of cyclic-AMP (cAMP), cyclic-GMP (cGMP) and protein kinase C (PKC) in modulating mucin-like glycoprotein secretion. Rat cornea sections (3 mm diameter) were cultured in TC-199 medium, and radiolabeled with sodium sulfate for 18 hr. After washing, the corneas were treated with various second messenger modulating agents for 30 min. The culture media were reacted with Dolichos biflorus (DBA)-lectin, and mucin-like glycoprotein was isolated. Then the radioactivity of DBA-binding mucin-like glycoprotein was isolated. Then the radioactivity of DBA-binding mucin-like glycoprotein was measured. There was a time-dependent increase in mucin-like glycoprotein was measured. There was a time-dependent increase in mucin-like glycoprotein secretion, whereas after corneal epithelial debridement the secretion was markedly inhibited by 81%. Mucin-like glycoprotein secretion was stimulated in a dose-dependent manner following elevation of cAMP levels by exposure to either forskolin, dibutyryl cAMP or 3-isobutyl-1-methylxanthine. Concomitant exposure to the cAMP dependent protein kinase inhibitor, KT5720 completely inhibited their stimulatory effects. Neither exposure to dibutyryl cGMP nor nitroprusside affected mucin-like glycoprotein secretion. Stimulation by PKC, phorbol 12, 13-dibutyrate (PDBu) also increased mucin-like glycoprotein secretion in a dose-dependent fashion. The PKC inhibitor, calphostin C completely inhibited the stimulation by PDBu of mucine-like glycoprotein secretion. These results demonstrate that corneal epithelial cells secrete mucin-like glycoprotein, which is mediated by cAMP and PKC signal transduction pathways.
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PMID:Mucin-like glycoprotein secretion is mediated by cyclic-AMP and protein kinase C signal transduction pathways in rat corneal epithelium. 962 98

Transgenic or knockout mouse models provide the opportunity to study the function of disease-related or novel genes. However, a confounding factor in all such research is the genetic and phenotypic variation of the mouse strain used to construct the models. A trait which is frequently studied in transgenic models of neurological disorders is synaptic transmission and plasticity of the dentate gyrus of the hippocampus. Consequently, we have investigated the variation in this trait across five strains of mouse (129 Ola, C3H, C57 albino, DBA/2, and FVB/N), in vivo. 129 Ola mice were found to have significantly larger maximal evoked EPSP slope and population spike amplitudes compared to the other strains. No differences across strains were found in paired-pulse facilitation of EPSP slope, a measure of pre-synaptic short-term plasticity. DBA/2 mice showed significantly reduced paired-pulse inhibition of population spike, a measure of poly-synaptic inhibitory feedback within the dentate gyrus. Potentiation of EPSP and population spike, following tetanic stimulation of the perforant path, was observed in all strains. However, DBA/2 mice showed a deficit in the maintenance of potentiation over 1 h, which confirms a previous report [S. Matsuyama, U. Namgung, A. Routtenberg, Long-term potentiation persistence greater in C57BL/6 than DBA/2 mice: predicted on basis of protein kinase C levels and learning performance, Brain Res. 763 (1997) 127-130]. These results show that electrophysiological traits do vary significantly across mouse strains, and that the selection of the strain may have a significant impact on results. Furthermore, since production of a transgenic or knock-out mouse frequently requires cross-breeding, care should be taken in establishing the contribution of parent strains to the final phenotype, as well as the potential interaction with the phenotype arising from the knock-out or transgene.
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PMID:Electrophysiological characterisation of the dentate gyrus in five inbred strains of mouse. 1054 95

DBA/2J (D2) mice display poor contextual learning and have less membrane-bound hippocampal protein kinase C (PKC) compared with C57BL/6 (B6) mice. Aniracetam and oxiracetam were previously shown to improve contextual learning in D2 mice and increase PKC activity. This study investigated a possible mechanism for learning enhancement by examining the effects of aniracetam on contextual fear conditioning and activation of the y isoform of PKC (gamma-PKC) in male D2 mice. In comparison to animals treated with vehicle only (10% 2-hydroxypropyl-beta-cyclodextrin), mice treated with aniracetam (100 mg/kg) 30 min prior to fear conditioning training demonstrated significantly improved contextual learning when tested 30 min and 24 h after training. This corresponded with a significant increase in activated, membrane-bound hippocampal gamma-PKC 30 min after training. No increase in learning or gamma-PKC was found 5 min after training. These results suggest an altered time course of activation of gamma-PKC in response to treatment with aniracetam, which improves learning in D2 mice.
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PMID:Aniracetam improves contextual fear conditioning and increases hippocampal gamma-PKC activation in DBA/2J mice. 1191 84

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

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

DBA/2J (D2) mice develop a form of progressive pigmentary glaucoma with increasing age. We have compared retinal cell populations of D2 mice with those in control C57BL/6J mice to provide information on retinal histopathology in the D2 mouse. The D2 mouse retina is characterized by a reduction in retinal thickness caused mainly by a thinning of the inner retinal layers. Immunocytochemical staining for specific inner retinal neuronal markers, viz., calbindin for horizontal cells; protein kinase C (PKC) and recoverin for bipolar cells, glycine, gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), and nitric oxide synthase (NOS) for amacrine cells, and osteopontin (OPN) for ganglion cells, was performed to detect preferentially affected neurons in the D2 mouse retina. Calbindin, PKC, and recoverin immunoreactivities were not significantly altered. Amacrine cells immunoreactive for GABA, ChAT, and OPN were markedly decreased in number, whereas NOS-immunoreactive amacrine cells increased in number. However, no changes were observed in the population of glycine-immunoreactive amacrine cells. These findings indicate a significant loss of retinal ganglion and some amacrine cells, whereas glycinergic amacrine cells, horizontal, and bipolar cells are almost unaffected in the D2 mouse. The reduction in amacrine cells appears to be attributable to a loss of GABAergic and particularly cholinergic amacrine cells. The increase in nitrergic neurons with the consequent increase in NOS and NO may be important in the changes in the retinal organization that lead to glaucomain D2 mice. Thus, the D2 mouse retina represents a useful model for studying the pathogenesis of glaucoma and mechanisms of retinal neuronal death and for evaluating neuroprotection strategies.
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PMID:Changes in retinal neuronal populations in the DBA/2J mouse. 1571 80

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary substrate of protein kinase C (PKC) thought to regulate membrane-filamentous actin cytoskeletal plasticity in response to PKC activity in the regulation of synaptic efficacy. We have recently reported that MARCKS expression is significantly elevated (45%) in the hippocampus of DBA/2J mice, which exhibit impaired hippocampus-dependent learning and hippocampal long-term potentiation (LTP), compared with C57BL/6J mice. The latter finding led us to hypothesize that elevations in MARCKS expression are detrimental to hippocampal plasticity and function. To assess this more directly, we examined hippocampal (CA1) paired-pulse facilitation and LTP, and hippocampus-dependent learning in mice overexpressing MARCKS through the expression of a human MARCKS transgene (Tg+). The human MARCKS protein was confirmed to be expressed in the hippocampus of Tg+ mice but not in Tg- mice. Schaffer collateral paired-pulse facilitation, input-output responses, and LTP did not differ between Tg+ and Tg- mice, indicating that neurotransmitter release, short-term, and long-term synaptic plasticity are not impaired by MARCKS overexpression. In the Morris water maze, Tg+ mice exhibited a mild but significant spatial learning impairment during initial acquisition, and a more severe impairment during reversal training. Tg+ did not exhibit impaired swim speed or visible platform performance relative to Tg- mice, indicating the absence of gross sensorimotor deficits. Fear conditioning to either context or cue was not impaired in Tg+ mice. Behavioral deficits could not be attributed to differences in hippocampal PKC isozyme (alpha beta(II), gamma, epsilon, zeta) or calmodulin expression, or alterations in hippocampal cytoarchitecture or infrapyramidal mossy fiber limb length. Collectively, these results indicate that elevations in MARCKS expression are detrimental to specific aspects of hippocampal function.
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PMID:Effect of myristoylated alanine-rich C kinase substrate (MARCKS) overexpression on hippocampus-dependent learning and hippocampal synaptic plasticity in MARCKS transgenic mice. 1588 47

We have demonstrated that an alternative C5a receptor (C5aR) ligand, the homodimer of ribosomal protein S19 (RP S19), contains a unique C-terminus (I(134)-H(145)) that is distinct from the moieties involved in the C5a-C5aR interaction. To examine the role of I(134)-H(145) in the ligand-C5aR interaction, we connected this peptide to the C-terminus of C5a (C5a/RP S19) and found that it endowed the second binding moiety of RP S19 (L(131)DR) with a relatively higher binding affinity to the C5aR on a human mast cell line, HMC-1. In contrast to the C5aR, the second C5aR C5L2 worked as a decoy receptor. As a result, the mitogen-activated protein kinase (MAPK) downstream of the Gi protein exchanged extracellular-signal regulated kinase for p38MAPK. This alternative p38MAPK activation could be pharmacologically suppressed not only by the downregulation of phosphoinositide 3-kinase (PI3K) by LY294002, but also by the over-activation of protein kinase C by phorbol 12-myristate 13-acetate. The activation was reproduced upon C5a-C5aR interaction by a simultaneous suppression of PI3K and phospholipase C with LY294002 and U73122 at low concentrations. Moreover, p38MAPK phosphorylation upstream of the pertussis toxin-dependent extracellular Ca(2+) entry was also suppressed by high concentrations of MgCl(2), which blocks melastatin-type transient receptor potential Ca(2+) channels (TRPMs). The active conformation of C5aR upon the ligation by C5a, at least on HMC-1 cells, is changed by the additional interaction of the I(134)-H(145) peptide, which seems to guide the alternative activation of p38MAPK. This activation is then amplified by a novel positive feedback loop between p38MAPK and TRPM.
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PMID:The role of the ribosomal protein S19 C-terminus in Gi protein-dependent alternative activation of p38 MAP kinase via the C5a receptor in HMC-1 cells. 2047 71

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABA(A) receptor (GABA(A)R) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol-consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol-consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABA(A)R inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABA(A)Rs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA(A)R responses to alcohol across rodent genotypes.
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PMID:Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity. 2416 56


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