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

Defective protein kinase C (PKC) has been implicated in impaired Na+,K(+)-ATPase activity in the sciatic nerve of streptozotocin-induced diabetic rats. In the present study, alpha, beta I, beta II, gamma, delta, and epsilon isoform-specific antibodies were used in parallel to the measurement of compound PKC activity for the characterization of PKC distribution and isoform expression in sciatic nerves of normal and diabetic rats. To distinguish isoform expression between the axonal and glial compartments, PKC isoforms were evaluated in nerves subjected to Wallerian degeneration and in a pure primary Schwann cell culture. alpha, beta I, beta II, delta, and epsilon but no gamma isoforms were detected in sciatic nerve. Similar immunoreactivity was observed in degenerated nerves 3-4 days after transection except for diminished beta I and epsilon species; in Schwann cell cultures, only alpha, beta II, delta, and epsilon were detected. In normal nerves, two-thirds of PKC compound activity was found in the cytosol and 50% of total enzyme activity translocated to the Na+,K(+)-ATPase-enriched membrane fraction with phorbol myristate acetate. Similar redistribution patterns were observed for the immunoreactivity of all isoforms with the exception of delta, which did not translocate to the membrane with phorbol myristate acetate. No abnormality in compound PKC activity, in the immunoreactive intensity, or in the distribution of PKC isoforms could be detected in rat sciatic nerve after 6-12 weeks of diabetes. Thus, defective activation rather than decreased intrinsic PKC activity may occur in diabetic neuropathy.
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PMID:Alpha, beta I, beta II, delta, and epsilon protein kinase C isoforms and compound activity in the sciatic nerve of normal and diabetic rats. 829 31

An in situ hybridization technique was applied to rat nervous tissues, to analyse the developmental changes in expression for the eta subtype mRNA of 14-3-3 protein, a putative regulatory protein for protein kinase C. Although signal levels of the eta subtype mRNA were low in mitotic cells in the ventricular zone, most neurons displayed a marked increase at their definitive location in the mantle zone. In general, neurons in the spinal ventral horn and peripheral ganglia showed this increase at E13-E15, those in the telencephalon, diencephalon, midbrain, pons and medulla oblongata at E18-P1, and the cerebellar Purkinje cells at P7-P14. It is at these developmental stages when neuronal differentiation including axonal and dendritic growth and ramification occurs actively. Subsequently high levels of the eta subtype mRNA were maintained until the adult stage in projection type neurons possessing larger cell bodies and highly developed dendritic fields, such as the olfactory mitral cells, hippocampal pyramidal cells, cerebellar Purkinje cells, and motor neurons in the brainstem and spinal cord. However, the signal levels decreased until the adult stage in smaller projection type neurons. On the other hand, the signal levels in local circuit type neurons were consistently low throughout development. These findings suggest that gene expression for the eta subtype mRNA of the 14-3-3 protein is regulated in close relation to both neuron types and their cytodifferentiation.
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PMID:Developmental regulation of neuronal expression for the eta subtype of the 14-3-3 protein, a putative regulatory protein for protein kinase C. 835 33

We have recently demonstrated that binding by monoclonal antibody (mAb) 8A2 to regenerating retinal ganglion cell axons in goldfish explants specifically induces a sustained, actin-based retraction response that is similar in most respects to a spontaneous retraction (S.G. Finnegan, V. Lemmon, and E. Koenig, Cell Motil. Cytoskeleton, 1992). Experiments were conducted to evaluate potential signal transduction pathways that may play a role in mediating retraction, using the mAb 8A2 retraction model system. Potential roles of cAMP, elevated intracellular calcium, or calmodulin-dependent processes were probed and the results did not appear to implicate them in either the induction or the maintenance of the axon retraction response. In contrast, treatment with phorbol 12-myristate 13-acetate, but not with inactive phorbol esters, induced a retraction response, although the response was more variable and less robust than that produced by mAb 8A2. However, both forms of induction were blocked by staurosporine, a nonspecific kinase inhibitor. Okadaic acid, a potent serine/threonine phosphatase inhibitor produced a very robust retraction response, and subthreshold doses significantly potentiated the retraction response induced by mAb 8A2. Genistein inhibited the mAb 8A2-induced retraction response at concentrations selective for tyrosine kinase activity in a dose-dependent manner. These findings are consistent with the hypothesis that an augmented phosphorylation state of one or more axonal proteins, perhaps catalyzed in part by protein kinase C, produces a sustained physiological retraction. In addition, tyrosine kinase may be involved in transducing surface-mediated interactions that trigger retraction, including the binding reaction signal of mAb 8A2.
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PMID:Monoclonal antibody 8A2-induced retraction appears to be mediated by protein phosphorylation in goldfish retinal ganglion cell axons. 838 19

The 43-kD growth-associated protein (GAP-43) is a major protein kinase C (PKC) substrate of axonal growth cones, developing nerve terminals, regenerating axons, and adult central nervous system areas associated with plasticity. It is a cytosolic protein associated with the cortical cytoskeleton and the plasmalemma. Membrane association of GAP-43 is mediated by palmitoylation at Cys3Cys4. In vitro and in vivo, phosphorylation by PKC exclusively involves Ser41 of mammalian GAP-43 (corresponding to Ser42 in the chick protein). To identify aspects of GAP-43 function, we analyzed the actions of wild-type, membrane-association, and phosphorylation-site mutants of GAP-43 in nonneuronal cell lines. The GAP-43 constructs were introduced in L6 and COS-7 cells by transient transfection. Like the endogenous protein in neurons and their growth cones, GAP-43 in nonneuronal cells associated with the cell periphery. GAP-43 accumulated in the pseudopods of spreading cells and appeared to interact with cortical actin-containing filaments. Spreading L6 cells expressing high levels of recombinant protein displayed a characteristic F-actin labeling pattern consisting of prominent radial arrays of peripheral actin filaments. GAP-43 had dramatic effects on local surface morphology. Characteristic features of GAP-43-expressing cells were irregular cell outlines with prominent and numerous filopodia. The effects of GAP-43 on cell morphology required association with the cell membrane, since GAP-43(Ala3Ala4), a mutant that failed to associate with the cell cortex, had no morphogenetic activity. Two GAP-43 phosphorylation mutants (Ser42 to Ala42 preventing and Ser42 to Asp42 mimicking phosphorylation by PKC) modulated the effects of GAP-43 in opposite ways. Cells expressing GAP-43(Asp42) spread extensively and displayed large and irregular membranous extensions with little filopodia, whereas GAP-43(Ala42) produced small, poorly spreading cells with numerous short filopodia. Therefore, GAP-43 influences cell surface behavior and phosphorylation modulates its activity. The presence of GAP-43 in growing axons and developing nerve termini may affect the behavior of their actin-containing cortical cytoskeleton in a regulatable manner.
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PMID:Phosphorylation-site mutagenesis of the growth-associated protein GAP-43 modulates its effects on cell spreading and morphology. 842 Oct 62

Human, macaque monkey, and rat retinas were immunostained with a polyclonal antibody preparation against purified recoverin, a 23-kD calcium-binding protein isolated from bovine retina that localizes to rods and cones (Dizhoor et al., 1991). In addition to immunoreactive photoreceptors, we have identified subpopulations of recoverin-positive bipolar cells in all three species. Results from immunostaining with progressive dilutions of anti-recoverin and preadsorption of the antibody with a dilution series of purified recoverin showed that photoreceptors and bipolar cells had similar affinities for the antibody and suggested that the molecule recognized by the antibody in both cell types is recoverin. Immunoreactivity for recoverin and protein kinase C, a selective marker for all rod bipolar cells, was found in separate bipolar cell populations. Recoverin immunoreactivity is therefore a characteristic of certain cone bipolar cell types. In rat retina, anti-recoverin labeled two morphologically distinct subpopulations of cone bipolar cells whose axonal arbors stratified at different depths in the inner plexiform layer (IPL). The bipolar cells labeled with anti-recoverin did not correspond to those that were reactive for calbindin, another cone bipolar cell marker. Human and monkey retinas also had two populations of cone bipolar cells that were recoverin-positive. One population showed a distinct pattern of narrow bistratification at the outer border of the IPL and a regular mosaic arrangement of its axonal arbors, suggesting that the entire population of a single cone bipolar type was labeled. Cell density, dendritic morphology, and axonal-field size and stratification indicate that anti-recoverin selectively strains the flat midget (presumed OFF-center) cone bipolar cell type observed previously in Golgi preparations. By contrast the second bipolar cell population had axonal stratification in the inner half of the IPL and showed an unusual but consistent morphology and spatial distribution. Individual cells were intensely stained but were present at an extremely low density (approximately 2-5 cells/mm2). These cells had multibranched dendritic trees characteristic of the diffuse bipolar cell class, but very small axonal fields in the size range of the midget bipolar class. Neither of the two recoverin-positive bipolar cell types in monkey was labeled with anti-calbindin or anti-cholecystokinin. An antibody preparation against bovine pineal hydroxyindole-O-methyltransferase (HIOMT) labeled photoreceptors and bipolar cells that closely resembled the recoverin-positive bipolar cells in human and rat retinas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recoverin immunoreactivity in mammalian cone bipolar cells. 842 20

During the 1980s, our view of airway hypersensitivity was altered significantly. Advances in biochemical techniques revealed involvement of several nonspecific events in nasal hyperreactivity: Autonomic dysfunction involving primary and/or secondary receptor disorders, epithelial damage by cytotoxic proteins in eosinophil, which is stimulated by inflammatory mediators, and an axonal reflex of sensory C fibers. Since 1983, we have neurobiochemically investigated the autonomic nerve dysfunction in the nasal mucosa of patients with nasal allergy and guinea pigs with experimentally-induced nasal hypersensitivity. We propose the following mechanisms as potential contributors to the disturbance of the beta receptor function in airway hyperreactivity: i) Down-regulation caused by excess endogenous norepinephrine stimulation, ii) down-regulation and uncoupling to adenylate cyclase, produced by the inflammatory mediator-induced activation of protein kinase C, iii) the action of beta receptor inhibitory factor, presumably anti beta receptor autoantibodies, and iv) dysfunction of beta receptor kinase, which is known to cause short-term desensitization of beta receptors after exposure to beta agonists. This review provides the anatomical and neurobiochemical background for the autonomic regulation and dysfunction in the nose. We also introduce our series of experiments and the above updated hypotheses of how functional disturbances of the autonomic nerve in the nasal mucosa may occur.
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PMID:Functional disturbances of the autonomic nerve in nasal hyperreactivity: an up-date review. 845 29

Monoclonal antibodies to the three isozymes of protein kinase C (PKC) (alpha, beta, and gamma) were applied to postmortem human retina. Immunostaining was done on wholemount, or cryostat-sectioned retina, and visualized after ABC/DAB procedures by light (LM) and electron (EM) microscopy. The PCK-alpha antibody stained rod bipolar cells throughout the retina. EM analysis confirmed they were PKC-alpha-immunoreactive (IR) on their characteristic dendritic and axonal synaptology. Putative blue cone bipolar cells with wide-field axon terminals, stratifying in s5 of the inner plexiform layer (IPL), were also PKC-alpha-IR, and EM showed them to engage in narrow-cleft ribbon junctions in blue cone pedicles. The PKC-beta antibody stained cone bipolar cells, many amacrine cells, and most ganglion cells. Cone bipolar cells were stained all the way into the foveal center: both midget and diffuse varieties were included. The IPL was densely PKC-IR and individual neurons could not be identified on stratification patterns. EM of the outer plexiform layer (OPL) revealed that both flat and invaginating cone bipolar types were IR and that IR axon terminals were presynaptic in all strata of the IPL. The occurrence of PKC-beta-IR bipolar axons in stratum 2 of the IPL suggests that OFF-center as well as ON-center types were included. The PKC-gamma antibody gave inferior staining compared with results from the other two antibodies; however, two varieties of wide-field monostratified amacrine cell and a large-bodied ganglion cell type were discernible. PKC in one form or another appears to be a second messenger used in neurotransmission by both rod and cone systems and ON- and OFF-center systems in the human retina.
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PMID:Differential staining of neurons in the human retina with antibodies to protein kinase C isozymes. 848 96

At least 50% of the major axonal membrane lipid, phosphatidylcholine, of rat sympathetic neurons is synthesized in situ in axons [Posse de Chaves, Vance, Campenot and Vance (1995) J. Cell Biol. 128, 913-918]. In the same study we reported that, in a choline-deficient model for neuron growth, phosphatidylcholine synthesis in cell bodies is neither necessary nor sufficient for growth of distal axons. Rather, the local synthesis of phosphatidylcholine in distal axons is required for normal axon growth. We have now used three alkylphosphocholines (hexadecylphosphocholine, dodecylphosphocholine and octadecylphosphocholine) as inhibitors of PtdCho biosynthesis in a compartmented model for culture of rat sympathetic neurons. The experiments reveal that alkylphosphocholines decrease the uptake of choline into these neurons and inhibit PtdCho synthesis, but not via an effect on the activity of the enzyme CTP: phosphocholine cytidylyltransferase. We also show that when the distal axons, but not the cell bodies, are exposed to alkylphosphocholines, axonal elongation is inhibited, which is consistent with the hypothesis that phosphatidylcholine synthesis in axons, but not in cell bodies, is required for axonal elongation. The inhibitory effect of alkylphosphocholines on axon growth is most likely not mediated via a decrease in the activity of protein kinase C, since when this enzyme activity is down-regulated by treatment of the cells with phorbol ester, the alkylphosphocholines retain their ability to inhibit axonal growth.
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PMID:Alkylphosphocholines inhibit choline uptake and phosphatidylcholine biosynthesis in rat sympathetic neurons and impair axonal extension. 852 49

Peripheral nerve regeneration comprises the formation of axonal sprouts, their outgrowth as regenerating axons and the reinnervation of original targets. This review focuses on the morphological features of axonal sprouts at the node of Ranvier and their subsequent outgrowth guided by Schwann cells or by Schwann cell basal laminae. Adhesion molecules such as N-CAM, L1 and N-cadherin are involved in the axon-to-axon and axon-to-Schwann cell attachment, and it is suggested that integrins such as alpha 1 beta 1 and alpha 6 beta 1 mediate the attachment between axons and Schwann cell basal laminae. The presence of synaptic vesicle-associated proteins such as synaptophysin, synaptotagmin and synapsin I in the growth cones of regenerating axons indicates the possibility that exocytotic fusion of vesicles with the surface axolemma supplies the membranous components for the extension of regenerating axons. Almost all the subtypes of protein kinase C have been localized in growth cones both in vivo and in vitro. Protein kinase C and GAP-43 are implicated to be involved in at least some part of the adhesion of growth cones to the substrate and their growth activity. The significance of tyrosine kinase in growth cones is emphasized. Tyrosine kinase plays an important role in intracellular signal transduction of the growth of regenerating axons mediated by both nerve trophic factors and adhesion molecules. Growth factors such as NGF, BDNF, CNTF and bFGF are also discussed mainly in terms of the influence of Schwann cells on regenerating axons.
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PMID:Peripheral nerve regeneration. 882 47

Developmental expression of alpha-, beta- and gamma-subspecies of protein kinase C in the dorsal corticospinal tract was immunohistochemically investigated at the cervical level of the postnatal rat spinal cord. On postnatal day 0, immunoreactivity for these subspecies was uniformly distributed throughout the posterior funiculus. On postnatal day 7, immunoreactivity for this enzyme in the posterior funiculus began to decline. On postnatal days 14 and 21, the immunoreactivity in the posterior funiculus became weak, while the dorsal corticospinal tract forming in the most ventral portion of the posterior funiculus exhibited strong immunoreactivity for these three subspecies of protein kinase C. Thereafter, immunoreactivity in the corticospinal tract rapidly declined, and on postnatal days 28 and 35, weak immunoreaction was demonstrated as very fine granular deposits in the tract. Expression of this enzyme in the dorsal corticospinal tract at these stages resembled that in the adult rat. Electron microscopically, growth cones and nascent axonal shafts were first noted on postnatal day 2 in the most ventral portion of the posterior funiculus, and thereafter, the axonal shaft gradually thickened and on postnatal day 14 some axons began to be myelinated. The growth cones and thin axonal shafts randomly exhibited weak immunoreactivity in the axoplasm. The thicker unmyelinated axonal shafts showed distinct immunoreactivity uniformly throughout the axoplasm and along the axolemma as granular deposits. In these developing axons, intensity and distribution of immunoreactivity for all three subspecies were principally similar. In the mature myelinated axons, the intensity and distribution of immunoreactivity for each subspecies of protein kinase C were quite different, i.e. immunoreactivity for alpha-subspecies was randomly distributed on some cytoskeletal elements, and that for beta-subspecies was uniformly detected on most of the cytoskeletal elements. In contrast, immunoreactivity for gamma-subspecies was distributed mainly on the endoplasmic reticulum. These findings suggest that in growing corticospinal axons protein kinase C might be involved in several important aspects of axonal development, and that in mature axons this enzyme might participate in different aspects of axonal function.
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PMID:Developmental expression of alpha-, beta- and gamma-subspecies of protein kinase C in the dorsal corticospinal tract in the rat spinal cord. 895 86


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