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)

Previous studies in our laboratory have demonstrated that exposure of rats to chronic lithium results in a significant reduction in the hippocampus of levels of the protein kinase C (PKC) phosphoprotein substrate MARCKS (myristoylated alanine-rich C kinase substrate), which persists after withdrawal and is not observed following acute administration. In an immortalized hippocampal cell line (HN33), we have determined that phorbol esters rapidly down-regulate PKC activity and lead to a subsequent PKC-dependent reduction in content of MARCKS protein. We now report that chronic exposure of HN33 cells to LiCl (1-10 mM) produces a dose- and time-dependent down-regulation of MARCKS protein. The lithium-induced reduction in MARCKS is dependent on the concentration of inositol present in the medium and is reversed and prevented in the presence of elevated inositol concentrations. When HN33 cells were exposed to lithium at clinically relevant concentrations (11 mM) under limiting inositol conditions, activation of muscarinic receptor-coupled phosphoinositide signaling significantly potentiated the lithium-induced down-regulation of MARCKS protein. It has been suggested that a major action of lithium in the brain is linked to its inositol monophosphatase inhibitory activity in receptor-mediated signaling through the inositol trisphosphate/diacylglycerol pathway, resulting in a relative inositol depletion. Our data provide evidence that this initial action of lithium may translate into a PKC-dependent long-term down-regulation of MARCKS protein expression in the hippocampus.
 ...
PMID:Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation. 876 6

Several lines of evidence indicate that a rapid loss of protein kinase C (PKC) activity may be important in the delayed death of neurons following cerebral ischemia. However, in primary neuronal cultures, cytotoxic levels of glutamate have been reported not to cause a loss in PKC as measured by immunoblot and conventional activity methods. This apparent contradiction has not been adequately addressed. In this study, the effects of cytotoxic levels of glutamate, NMDA, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on membrane PKC activity was determined in cortical neurons using an assay that measures only PKC that is active in isolated membranes, which can be used to differentiate active enzyme from that associated with membranes in an inactive state. A 15-min exposure of day 14-18 cortical neurons to 100 microM glutamate, AMPA, or NMDA caused a rapid and persistent loss in membrane PKC activity, which by 4 h fell to 30-50% of that in control cultures. However, the amount of enzyme present in these membranes remained unchanged during this period despite the loss in enzyme activity. The inactivation of PKC activity was confirmed by the fact that phosphorylation of the MARCKS protein, a PKC-selective substrate, was reduced in intact neurons following transient glutamate treatment. By contrast, activation of metabotropic glutamate receptors by trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid was not neurotoxic and induced a robust and prolonged activation of PKC activity in neurons. PKC inactivation by NMDA and AMPA was dependent on extracellular Ca2+, but less so on Na+, although cell death induced by these agents was dependent on both ions. The loss of PKC activity was likely effected by Ca2+ entry through specific routes because the bulk increase in intracellular free [Ca2+] effected by the Ca2+ ionophore ionomycin did not cause the inactivation of PKC. The results indicate that the pattern of PKC activity in neurons killed by glutamate, NMDA, and AMPA in vitro is consistent with that observed in neurons injured by cerebral Ischemia in vivo.
 ...
PMID:An early loss in membrane protein kinase C activity precedes the excitatory amino acid-induced death of primary cortical neurons. 876 54

The myristoylated alanine-rich C kinase substrate, or MARCKS protein, is a widely expressed, prominent substrate for protein kinase C. Although the exact function of MARCKS has not been elucidated, targeted disruption of the MARCKS gene (Macs) in mice has shown that MARCKS plays a crucial role in the development of the central nervous system. Mice deficient in MARCKS exhibited universal perinatal death with defects in neurulation, fusion of the cerebral hemispheres, formation of the great forebrain commissures, and retinal and cortical lamination (Stumpo et al., Proc. Natl. Acad. Sci. USA 92, 944-948, 1995). In the present studies, a transgene consisting of approximately 3.4 kb of promoter from the human MARCKS gene (MACS), with an epitope tag sequence inserted at the carboxyl terminus of the MARCKS coding region, was able to complement completely MARCKS deficiency in mice. Thus, the human transgene contained all of the elements necessary for normal developmental expression of MARCKS. To test the importance of MARCKS myristoylation to its developmental role, an otherwise identical transgene was constructed in which the glycine at the amino terminus of MARCKS was mutated to an alanine. This mutation, which resulted in the expression of nonmyristoylated MARCKS, was successful in partially rescuing the Macs null phenotype. Specifically, about 25% of these mice survived the perinatal period; these survivors appeared to develop normally except for slightly decreased body size. In both the survivors and the nonsurvivors, all of the known anatomical defects associated with MARCKS deficiency were corrected by expression of the nonmyristoylated human protein. These results indicate that myristoylation of MARCKS is not required for the protein to correct many of the developmental abnormalities characteristic of its deficiency.
 ...
PMID:Nonmyristoylated MARCKS complements some but not all of the developmental defects associated with MARCKS deficiency in mice. 887 59

The roles of protein kinase C and its substrates in development are poorly understood. Recently, we disrupted the mouse gene for a major cellular substrate for protein kinase C, the MARCKS protein (Proc. Natl. Acad. Sci. USA, 92, 944-948, 1995). The resulting phenotype consisted of universal perinatal lethality, agenesis of the corpus callosum and other forebrain commissures, and neuronal ectopia and other cortical and retinal lamination disturbances. These mice also had high frequencies of exencephaly (25% overall, 35% in females). In the present study, we have examined the normal expression of MARCKS and the various isozymes of protein kinase C at the time of cranial neural tube closure, in an attempt to correlate MARCKS expression in time and anatomical location with the exencephaly characteristic of MARCKS deficiency. Failure of neural tube closure occurred at various sites in the cranial neural tube, suggesting a cellular functional defect that was not limited to a specific location. Non-exencephalic MARCKS-deficient embryos appeared to be anatomically normal on embryonic day (E) 8.5-9.5. MARCKS and PKC alpha were expressed at the plasma membrane of the neuroepithelial cells comprising the future neural tube, as well as in the surface ectoderm and underlying mesenchyme. Endogenous protein kinase C species, comprising either or both alpha and delta, were capable of phosphorylating MARCKS in intact E8.5 embryos. Thus, MARCKS is expressed at the plasma membranes of the specific cell types involved in cranial neurulation; its deficiency presumably results in a still-to-be-elucidated functional defect in these cells that leads to exencephaly in a high proportion of cases.
 ...
PMID:Developmental expression of MARCKS and protein kinase C in mice in relation to the exencephaly resulting from MARCKS deficiency. 892 69

The effects of the food-borne mutagenic and carcinogenic heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), on the proliferation of murine spleen cells was examined. A significant and dose-related suppression of the proliferative response to concanavalin A (Con A) was observed by the treatment of IQ. IQ also decreased markedly the level of proliferative response induced by PMA and ionomycin and the IL-2 secretion by T cells. Treatment of PMA resulted in the recovery of IQ-induced suppression of IL-2 production, but the addition of ionomycin (Io) had no effect. IQ decreased PKC activity in both the membrane fraction and the cytosol fraction and inhibited the phosphorylation of MARCKS protein. These results suggest that the suppression of spleen cell proliferation induced by IQ might be associated with the inhibition of PKC activity and the subsequent IL-2 secretion of T cells.
 ...
PMID:2-amino-3-methylimidazo[4,5-f]quinoline-mediated immunosuppression involves inhibition of protein kinase C in murine splenocytes. 894 11

We have recently shown that AVP causes a protein kinase C (PKC)-dependent increase in ACTH release and biosynthesis in ovine anterior pituitary cells. In these cells, AVP also causes the translocation of PKC from the cytosol to the cell membrane which is maximal at 5 min, but the intracellular events distal to protein kinase C activation that underlie ACTH secretion have not been well characterized to date. Since the MARCKS protein has been implicated in neurosecretion and is phosphorylated by PKC in synaptosomes, studies were carried out to determine whether AVP might cause MARCKS phosphorylation in the ovine anterior pituitary, and to determine whether this phenomenon might be temporally correlated with PKC translocation and the release of ACTH. When cytosolic fractions of rat brain, ovine anterior pituitary, and cultured ovine anterior pituitary cells were incubated with purified PKC, several proteins were phosphorylated including those in the region of 83-85 kDa. After precipitation of the proteins with 40% acetic acid, the 83-85 kDa phosphoproteins were selectively recovered in the acid soluble phase. Phosphopeptide maps of either the 83 or 85 kDa proteins were generated with Staphylococcus aureus V8 protease and revealed 13 and 9 kDa phosphopeptides, which are characteristic of the authentic MARCKS protein. An identical phosphopeptide map was also obtained when the MARCKS protein was selectively extracted from intact 32P-labeled anterior pituitary cells. MARCKS phosphorylation was markedly increased when ovine anterior pituitary cells were exposed to 1 microM phorbol 12-myristate 13-acetate (PMA). When the cells were exposed to 1 microM AVP, MARCKS phosphorylation increased at 15 s and reached the maximal plateau value at 30 s. MARCKS phosphorylation then started to diminish at 2 min, and baseline levels were attained by 10 min. In the same cells, AVP stimulated ACTH release in a biphasic manner - during the first 30 s, there resulted a rapid burst of ACTH secretion that was followed by a slower, but sustained rate of secretion. We conclude that: (1) AVP causes a rapid, and reversible, phosphorylation of the MARCKS protein in the ovine anterior pituitary; (2) since the AVP-induced increase in MARCKS phosphorylation occurs much earlier in these cells than does PKC trans-location, MARCKS phosphorylation may provide a more sensitive index of the onset of PKC activation than the translocation assay; (3) the close temporal association between MARCKS phosphorylation and the rapid early release of ACTH suggests that MARCKS phosphorylation may be involved in the initial intracellular events that underly exocytosis of the hormone.
 ...
PMID:Arginine vasopressin (AVP) causes the reversible phosphorylation of the myristoylated alanine-rich C kinase substrate (MARCKS) protein in the ovine anterior pituitary: evidence that MARCKS phosphorylation is associated with adrenocorticotropin (ACTH) secretion. 939 59

Sodium valproate (VPA) is a short-chain fatty acid with well-established anticonvulsant properties and apparent clinical efficacy in the treatment of bipolar disorder (manic-depressive illness). Little is known regarding the mechanism of action of VPA in the brain that could account for this clinical therapeutic profile. Lithium has been the standard treatment for bipolar disorder, and it is known to be an uncompetitive inhibitor of inositol monophosphatase in the phosphoinositide (PI) signaling cascade at clinically relevant concentrations. Recent studies have provided data in support of a role for protein kinase C and the down-regulation of expression of the myristoylated alanine-rich C kinase substrate (MARCKS) in the long-term therapeutic action of lithium in the brain, which is dependent on both the relative activity of receptor-coupled PI signaling and the concentration of myo-inositol. Our current results demonstrated that valproate induces a concentration- and time-dependent reduction of MARCKS in immortalized hippocampal cells that appears to be independent of both the level of muscarinic receptor-activated PI signaling as well as the concentration of myo-inositol. In CHO-K1 cells transfected with the human m1 muscarinic receptor, unlike lithium, there is no evidence for receptor-mediated accumulation of CMP-PA in the presence of VPA, providing more direct data for its lack of interaction within the PI signaling cascade. The action of VPA on MARCKS occurs within the therapeutic concentrations and time course observed in clinical studies of patients with bipolar disorder. Furthermore, the effect on MARCKS protein is additive in the presence of therapeutic concentrations of both lithium and valproate, consistent with clinical observations regarding the enhanced efficacy of the combination treatment. Finally, in studies examining acute and chronic effects of a variety of psychotropic compounds and VPA structural analogs, it is evident that the property of regulation of MARCKS is shared by the mood-stabilizers lithium and VPA, which may be specific to a class of drugs effective in the treatment of bipolar disorder.
 ...
PMID:Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate (MARCKS) in immortalized hippocampal cells: a property of protein kinase C-mediated mood stabilizers. 953 26

Although growth cones respond to various modulators of neurite outgrowth, such as neurotrophins, neurotransmitters, and cell adhesion molecules, the signal-transducing mechanisms for these modulators in growth cones are unclear. Since recent studies have suggested that the signals of these modulators are mediated by Ca2+ influx through L-type voltage-sensitive Ca2+ channels (VSCCs) in the growth cone, we examined L-type VSCC-dependent signaling pathways, using isolated growth cones (IGCs) from developing rat forebrains. Binding assays revealed that L-type VSCC is enriched in growth cone membrane and gradually decreased in amount developmentally, while N-type VSCC has the opposite tendency. In intact IGCs, Bay K 8644 (BK, an L-type agonist) induced much more rapid elevation of [Ca2+]i than that in adult synaptosomes. Ca2+-dependent phosphorylation of GAP-43 and MARCKS protein by protein kinase C (PKC) was enhanced in the IGC by BK, resulting in the release of these proteins from the membrane, which is consistent with our recent report. In addition, the Ca2+-dependent degradation of brain spectrin (fodrin) by calpain was also enhanced by BK or GABA, consequently inducing the release of alpha-actinin from the membrane skeleton of the growth cones. The activities of PKC and calpain were not inhibited by inhibitors of the other, indicating that these reactions occur independently. Our results suggest that Ca2+ influx through L-type VSCCs activates two distinct signaling branches, probably in the different domains of the growth cone, i.e., Ca2+-dependent phosphorylation of GAP-43 and MARCKS protein, and Ca2+-dependent degradation of brain spectrin and the release of alpha-actinin by calpain.
 ...
PMID:Stimulation of L-type Ca2+ channel in growth cones activates two independent signaling pathways. 954 83

Diacylglycerol kinases (DGKs) terminate signalling from diacylglycerol by converting it to phosphatidic acid. Diacylglycerol regulates cell growth and differentiation, and its transient accumulation in the nucleus may be particularly important in this regulation. Here we show that a fraction of DGK-zeta is found in the nucleus, where it regulates the amount of nuclear diacylglycerol. Reducing nuclear diacylglycerol levels by conditional expression of DGK-zeta attenuates cell growth. The nuclear-localization signal of DGK-zeta is located in a region that is homologous to the phosphorylation-site domain of the MARCKS protein. This is, to our knowledge, the first evidence that this domain, which is a major target for protein kinase C, can localize a protein to the nucleus. Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. Our results define a cycle in which diacylglycerol activates protein kinase C, which then regulates the metabolism of diacylglycerol by alternating the intracellular location of DGK-zeta. This may be a general mechanism to control mitogenic signals that depend on nuclear diacylglycerol.
 ...
PMID:Protein kinase C regulates the nuclear localization of diacylglycerol kinase-zeta. 971 25

It is widely assumed that the members of the MARCKS protein family, MARCKS (an acronym for myristoylated alanine-rich C kinase substrate) and MARCKS-related protein (MRP), interact with actin via their effector domain, a highly basic segment composed of 24-25 amino acid residues. To clarify the mechanisms by which this interaction takes place, we have examined the effect of a peptide corresponding to the effector domain of MRP, the so-called effector peptide, on both the dynamic and the structural properties of actin. We show that in the absence of cations the effector peptide polymerizes monomeric actin and causes the alignment of the formed filaments into bundle-like structures. Moreover, we document that binding of calmodulin or phosphorylation by protein kinase C both inhibit the actin polymerizing activity of the MRP effector peptide. Finally, several effector peptides were synthesized in which positively charged or hydrophobic segments were deleted or replaced by alanines. Our data suggest that a group of six positively charged amino acid residues at the N-terminus of the peptide is crucial for its interaction with actin. While its actin polymerizing activity critically depends on the presence of all three positively charged segments of the peptide, hydrophobic amino acid residues rather modulate the polymerization velocity.
 ...
PMID:Interaction between actin and the effector peptide of MARCKS-related protein. Identification of functional amino acid segments. 1074 10


<< Previous 1 2 3 4 5 6 7 8 9 Next >>