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 axonal guidance and outgrowth in retinal neurons were investigated in cultures of pure retinal neurons (control) or in cocultures with heterologous BC3H-1 cells. Under control conditions, only about 10% of retinal neurons developed axons; coculturing with BC3H-1 cells induced early axonal outgrowth and guidance to BC3H-1 cells in most amacrine neurons. Both mechanisms were dependent on laminin and neural cell-adhesion molecules (N-CAMs) released by BC3H-1 cells, because they were prevented by antibodies directed against these molecules. The protein kinase C (PKC) inhibitor, staurosporine, reduced the effect of laminin on amacrine axonal outgrowth, suggesting that this effect was mediated by PKC. The occurrence of structures resembling synaptic boutons and the expression of synaptophysin at the amacrine axon ends of heterologous connections suggested that amacrine axons establish true synaptic contacts rather than simply overlapping with the BC3H-1 cells. In contrast to the heterologous contacts with BC3H-1 cells, the amacrine-amacrine axonal contacts observed in the cocultures were independent of laminin and N-CAM. Axonal outgrowth occurred in about 10% of the photoreceptors and was not affected by BC3H-1 cells or by substratum pretreatment with laminin or N-CAM. These results show that different mechanisms affect axonal outgrowth and guidance in amacrine and photoreceptor neurons in vitro, and they suggest that similar mechanisms could contribute to the development of the scaffold of axon pathways in the retina in vivo.
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PMID:Selective outgrowth and differential tropism of amacrine and photoreceptor axons to cell targets during early development in vitro. 955 33

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white matter lesions mimicking periventricular leukomalacia, the most frequent brain lesion occurring in premature human babies. In this model, coinjection of vasoactive intestinal peptide prevents white matter lesions. In the present study, coadministration of ibotenate, vasoactive intestinal peptide, and selective transduction inhibitors showed that protein kinase C and mitogen-associated protein kinase pathways were critical for neuroprotection. In vivo and in vitro immunocytochemistry revealed that vasoactive intestinal peptide activated protein kinase C in astrocytes and neurons, and mitogen-associated protein kinase in neurons. In vitro neuronal transduction activation was indirect and required medium conditioned by astrocytes in which protein kinase C had been activated by vasoactive intestinal peptide. Although vasoactive intestinal peptide did not prevent the initial in vivo appearance of white matter lesion, it promoted a secondary repair of this lesion with axonal regrowth. Through protein kinase C activation, vasoactive intestinal peptide also prevented ibotenate-induced white matter astrocyte death. These data support the following hypothetical model: Vasoactive intestinal peptide activates protein kinase C in astrocytes, which promotes astrocytic survival and release of soluble factors; these released factors activate neuronal mitogen-associated protein kinase and protein kinase C, which will permit axonal regrowth.
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PMID:Regulation of neuroprotective action of vasoactive intestinal peptide in the murine developing brain by protein kinase C and mitogen-activated protein kinase cascades: in vivo and in vitro studies. 960 24

Gz is the only pertussis-toxin-insensitive member of the inhibitory G protein subfamily. The unique pattern of tissue distribution of Gz suggests it may carry out tissue-specific functions, albeit it appears to share the same profile of G-protein-coupled receptors with Gi. The knowledge of the structural elements of alpha z for receptor coupling and specificity has been enriched by constructing chimeric molecules. Biochemical characteristics of alpha z are considerably different from other G protein alpha-subunits. The regulation of the GTP hydrolysis activity of alpha z by various GTPase-activating proteins and the functional impact of the PKC-mediated phosphorylation of alpha z are discussed. Different routes of signaling pathways that Gz could engage in have been explored. Furthermore, the possible involvement of Gz in retrograde axonal transport and various immune responses shed lights in understanding the physiological importance of Gz.
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PMID:Structure and function of the pertussis-toxin-insensitive Gz protein. 962 59

This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.
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PMID:Neurofilaments in health and disease. 975 17

By the yeast two-hybrid screening of a rat brain cDNA library with the regulatory domain of protein kinase C zeta (PKCzeta) as a bait, we have cloned a gene coding for a novel PKCzeta-interacting protein homologous to the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth and fasciculation. The protein designated FEZ1 (fasciculation and elongation protein zeta-1) consisting of 393 amino acid residues shows a high Asp/Glu content and contains several regions predicted to form amphipathic helices. Northern blot analysis has revealed that FEZ1 mRNA is abundantly expressed in adult rat brain and throughout the developmental stages of mouse embryo. By the yeast two-hybrid assay with various deletion mutants of PKC, FEZ1 was shown to interact with the NH2-terminal variable region (V1) of PKCzeta and weakly with that of PKCepsilon. In the COS-7 cells coexpressing FEZ1 and PKCzeta, FEZ1 was present mainly in the plasma membrane, associating with PKCzeta and being phosphorylated. These results indicate that FEZ1 is a novel substrate of PKCzeta. When the constitutively active mutant of PKCzeta was used, FEZ1 was found in the cytoplasm of COS-7 cells. Upon treatment of the cells with a PKC inhibitor, staurosporin, FEZ1 was translocated from the cytoplasm to the plasma membrane, suggesting that the cytoplasmic translocation of FEZ1 is directly regulated by the PKCzeta activity. Although expression of FEZ1 alone had no effect on PC12 cells, coexpression of FEZ1 and constitutively active PKCzeta stimulated the neuronal differentiation of PC12 cells. Combined with the recent finding that a human FEZ1 protein is able to complement the function of UNC-76 necessary for normal axonal bundling and elongation within axon bundles in the nematode, these results suggest that FEZ1 plays a crucial role in the axon guidance machinery in mammals by interacting with PKCzeta.
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PMID:Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein. 997 36

We investigated roles of protein kinase C (PKC) and Ca2+/calmodulin-dependent protein II (CAM II) kinase activities in the maintenance of axonal transport in cultured isolated mouse dorsal root ganglion (DRG) cells. Video-enhanced microscopic recordings revealed that the PKC inhibitor chelerythrine (1 microM) reduced anterograde and retrograde axonal transport, while the CAM II kinase inhibitor KN-62 (10 microM) had no effect. Morphological observation showed that neurite growth was prevented by the presence of chelerythrine (1 microM). From these results, we conclude that PKC activity is required to maintain axonal transport and thereby neurite growth.
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PMID:Axonal transport is inhibited by a protein kinase C inhibitor in cultured isolated mouse dorsal root ganglion cells. 1021 5

Axonal contact regulates Schwann cell (SC) proliferation during development. However, the intracellular signal transduction pathways involved in the axon-induced proliferation of SC have not been described. We have previously shown that SC proliferation induced by axolemma-enriched fractions (AEF) is accompanied by increased expression of cyclic AMP-responsive element binding protein, CREB. We now report the AEF and dorsal root ganglion neuritic-induced signal transduction pathway(s) which regulate the phosphorylation of CREB that correlate with the SC proliferative response. The phosphorylated form of CREB was significantly increased after 16 hr of axonal stimulation, continued to increase for 48 hr, and subsequently decreased as monitored by immunocytochemistry and Western blot analysis. Treatment with protein kinase A (PKA) inhibitor, H89, completely abolished both the CREB activation and SC proliferation. In contrast, treatment with protein kinase C (PKC) inhibitor (bisindolylmaleimide) inhibited AEF-induced SC proliferation, but did not immediately affect CREB phosphorylation. These data are consistent with the view that PKA and PKC pathways are essential for AEF-induced SC proliferation. Since PKC can influence SC proliferation without initially affecting CREB phosphorylation, PKC may regulate SC proliferation at pathways distal to the immediate CREB activation.
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PMID:Phosphorylation of CREB in axon-induced Schwann cell proliferation. 1022 Jan 11

We have stained a new population of bipolar cells in rabbit retina by using antibodies against the carbohydrate epitope, CD15. The CD15-positive bipolar cells comprise 6-8% of the total cone bipolar cells in peripheral retina. Their axonal and dendritic arbors are similar in size and range from 15 to 50 pm in diameter. The axonal arbors are narrowly stratified in sublamina b of the inner plexiform layer. Double label experiments using an antibody against the calcium binding protein, calbindin, or an antibody against protein kinase C, demonstrate that the CD15-positive bipolar cells are a separate population from the previously identified calbindin-positive cone bipolar cells and the rod bipolar cells. Labeling the processes of starburst amacrine cells with antibodies against choline acetyltransferase showed that the CD15-positive bipolar cells stratify within and slightly more distally to the processes of the ON-starburst amacrine cells. Confocal images of retinal wholemounts showed that the axons of the CD15-positive bipolar cells follow the pattern of the ON-starburst cells' processes. Axonal varicosities of the CD15-positive bipolar cells penetrate the bundles formed by the processes of the ON-starburst cells. This finding suggests that the CD15-positive bipolar cell provides input to the ON-starburst amacrine cells and/or the ON-plexus of the ON-OFF direction-selective ganglion cells.
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PMID:Costratification of a population of bipolar cells with the direction-selective circuitry of the rabbit retina. 1033 82

The growth cone is responsible for axonal elongation and pathfinding by responding to various modulators for neurite growth, including neurotransmitters. We demonstrated an outline of the gamma aminobutyric acid (GABA)(A)-dependent signaling in growth cones. Here, we examined the effects of the modulators of GABA(A) receptor on the signaling in growth cones. Phenobarbital or propofol, acting on beta-subunit, enhanced the [Cl(-)]infi change and [Ca(2+)](i) elevation by the GABA stimulation to isolated growth cones. Besides, propofol enhanced GABA-dependent phosphorylation of growth-associated protein of 43 kDa (GAP-43) by protein kinase C. In contrast, an alpha-subunit acting agent diazepam did not modulate any of the above signals. Next, we examined the effect of the developmental change of alpha-subunit on the outline of the GABA(A)-dependent signaling in growth cones. We also found that the amounts of several different alpha-subunit isoforms developmentally increased or decreased in growth cone membrane (GCM), but that the affinity and density of the [(3)H]diazepam binding sites were similar to those in adult synaptic membrane. Taken together, our results strongly suggest that each step of GABA(A)-dependent signaling in GCM is not modified by diazepam, indicating that the signaling pathway mediated by GABA(A) receptor in growth cones is applicable to any compositional change of alpha-subunit isoforms.
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PMID:GABA(A) receptor in growth cones: the outline of GABA(A) receptor-dependent signaling in growth cones is applicable to a variety of alpha-subunit species. 1051 14

In spinal cord explant cultures from embryonic chicken (E7) we found that both a long-time downregulation of PKC by phorbol-12,13-dibutyrate (PDBu) and an inhibition of PKC by RO-31-8220 strongly reduce neurite outgrowth. Unlike this, in the presence of a high dose of 1,2-dioctanoyl-s,n-glycerol (diC8, 60 microM), PKCalpha,beta isoforms are not downregulated, but neurite outgrowth appeared reduced up to 37 %. A low dose of diC8 (5 microM), however, was found to stimulate neurite outgrowth up to 25 %. Using this tissue culture system as well as neuronal cell culture we then studied the effects of diC8 on the shapes and actin-based motility of distal axonal processes and growth cones as well as on the spatial distribution of f-actin and serine 41-phosphorylated GAP-43 (neuromodulin, B50). High-resolution microscopy showed that addition of 30-60 microM diC8 leads within a few minutes to a retraction of filopodia and to an increased protrusion of lamellipodia followed by the formation of club-shaped dense growing tips, axonal varicosities, and a cessation of any actin dynamics. These striking shape changes are completely reversed after replacement of the medium by drug-free medium. Presence of cytochalasins and a panel of different PKC inhibitors prevent or respectively attenuate the diC8 effects. Immuno- and phalloidin-staining confirmed that in control neurons f-actin and serine 41-phosphorylated GAP-43 are confined to and enriched in the growth cones. In parallel with diC8-induced shape changes there is an accretion of f-actin and serine 41-phosphorylated GAP-43 in the entire axonal processes and the rounded growing tips. With respect to the fundamental role of the actin dynamics in growth cone steering and neuronal pathfinding, the data supports the view that in neurons local PKC-regulated phosphorylation of GAP-43 may represent an important mechanism to transduce guiding signals into actincytoskeletal responses mediating directed axonal growth.
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PMID:1,2-dioctanoyl-s,n-glycerol-induced activation of protein kinase C results in striking, but reversible growth cone shape changes and an accumulation of f-actin and serine 41-phosphorylated GAP-43 in the axonal process. 1056 42


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