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)

In a rat model of morphine tolerance, we examined the hypotheses that thermal hyperalgesia to radiant heat develops in association with the development of morphine tolerance and that both the development and expression of thermal hyperalgesia in morphine-tolerant rats are mediated by central NMDA and non-NMDA receptors and subsequent protein kinase C (PKC) activation. Tolerance to the analgesic effect of morphine was developed in rats utilizing an intrathecal repeated treatment regimen. The development of morphine tolerance and thermal hyperalgesia was examined by employing the tail-flick test and paw-withdrawal test, respectively. Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine-tolerant rats. Tolerance to the analgesic effect of morphine was reliably developed in rats following once daily intrathecal (onto the lumbosacral spinal cord) injection of 10 micrograms of morphine sulfate for 8 consecutive days as demonstrated by the decreased analgesia following morphine administration on day 8 as compared to that on day 1. In association with the development of morphine tolerance, thermal hyperalgesia to radiant heat developed in these same rats. Paw-withdrawal latencies were reliably decreased in morphine-tolerant rats as compared to nontolerant (saline) controls when tested on day 8 before the last morphine treatment and on day 10 (i.e., 48 hr after the last morphine treatment). The coincident development of morphine tolerance and thermal hyperalgesia was potently prevented by intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160 nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol) and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably reversed thermal hyperalgesia in rats rendered tolerant to morphine when tested 30 min after each drug treatment on day 10 (48 hr after the last morphine treatment). The data indicate that thermal hyperalgesia develops in association with the development of morphine tolerance and that the coactivation of central NMDA and non-NMDA receptors is crucial for both the development and expression of thermal hyperalgesia in morphine-tolerant rats. Furthermore, intracellular PKC activation plays a critical role in the development of thermal hyperalgesia in morphine-tolerant rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. 790 58

The activity of transglutaminase (TG), a Ca(2+)-dependent enzyme indicating tissue degradation or differentiation, showed in isolated adult rat superior cervical ganglia (SCG) a rapid (within 15 to 30 min) and marked (approx. 5- to 8-fold) increase with the addition of either GM1 ganglioside (GM1, 5 nM), which is rich in synapses, or sialyl cholesterol (SC, 20 microM), a synthetic sialic acid-containing compound, to the incubation medium at 37 degrees C. Under the same incubation conditions, addition of GM1 or SC decreased protein kinase C (PKC) activity (-26% to -39%) in the cytosolic fraction of the SCG, but increased the enzymic activity (+39% to +61%) in the particulate (cell membrane) fraction, suggesting that a sialic acid-containing compound (GM1 or SC) promotes PKC translocation from the cytosol to the membrane in ganglionic neurons. By contrast, addition of a promoting factor for survival of sympathetic neurons even in adulthood, nerve growth factor, (NGF, 0.25 micrograms/ml) to the medium significantly decreased ganglionic TG activity (-43%). This inhibition was completely antagonized by the co-addition of NGF-monoclonal antibody (0.75 microgram/ml). An effective blockade of GM1- or SC-induced stimulation of ganglionic TG activity was seen by further addition of NGF to the medium. Also, NGF almost abolished the translocation of ganglionic PKC activity induced by the sialic acid-containing compounds, although either NGF or 12-O-tetradecanoylphorbol ester (TPA) alone stimulated the cytosolic PKC activity (approx. +30%) in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blockade effect of nerve growth factor on GM1 ganglioside-induced activation of transglutaminase in superior cervical sympathetic ganglia excised from adult rat. 791 48

Surface expression of the CD4 glycoprotein molecule is postulated to facilitate antigen recognition through the T cell receptor (TCR) and is itself a receptor for human immunodeficiency virus (HIV)-gp120 glycoprotein. Both antigen-stimulated TCR activation and HIV infectivity can be blocked by whole anti-CD4 antibodies. Although selective modulation of CD4 from the surface by gangliosides (GM1) blocks HIV infectivity, it enhances associated TCR function. Enhanced TCR function has also been observed after intracellular delivery of synthetic CD4 mRNA-antisense oligodeoxynucleotides (ODN) that block de novo synthesis of CD4. These specific CD4 modulations were mechanistically different from one another yet they both selectively removed the CD4 molecule from the T cell surface and enhanced antigen-stimulated function through the TCR. The proposed role of CD4 during TCR function and HIV infectivity was developed, in part, according to decreases following CD4 antagonism by whole antibody or down-modulation of CD4 by phorbol-stimulated protein kinase C activity. Selective CD4 modulations have independently redefined the specific contributions of CD4 surface expression during T cell activation and may establish a role for CD4 receptor subtypes during HIV-1 infection of CD4+ cells.
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PMID:Understanding the CD4 molecule: surface expression and function. 805 86

The barrier function of endothelial cells is known to be positively regulated by protein kinase A (PKA) and negatively regulated by protein kinase C (PKC). We found that exogenously administered GM3(NeuAc) promoted PKA activity in cultured brain microvascular endothelial cells (BMECs). Other glycolipids, including GM1, sulfoglucuronyl paragloboside, and GM3(NeuGc), did not have any effect on the PKA activity of BMECs. PC12 cells did not respond to exogenously applied GM3(NeuAc). GM3(NeuAc) also suppressed the PKC activity of BMECs. Thus, GM3(NeuAc) may function as a modulator of blood-brain barrier function via the two different kinase systems.
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PMID:GM3 regulates protein kinase systems in cultured brain microvascular endothelial cells. 822 5

Four new deacylated lysogangliosides were obtained through alkaline hydrolysis of either C18 or C20 sphingosine homologues of GM1. By this procedure, both the fatty acids residue and the N-acetyl group of sialic acid were removed to give mono-N-acetyl-lysoGM1 (C18 and C20); the additional loss of the N-acetyl group of the acetylgalactosamine moiety gave de-N-acetyl-lysoGM1 (C18 and C20) with three free amino groups. The structures of four deacetylated lysogangliosides were unambiguously characterized by chemical analysis and 1H and 13C NMR spectroscopy as well as by negative ion FABMS. The aim of this study was to isolate pure breakdown products of gangliosides, enabling the evaluation of the mechanism of action of glycosphingolipids through their cleavage and identification of structures of potential pharmacological activity. These new substances were prepared as candidates to influence eicosanoid production and the mechanisms dependent on protein kinase C and phospholipase A2.
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PMID:Preparation and characterization of four new variously deacetylated lysogangliosides, breakdown products of GM1. 825 37

Phorbol esters, which activate protein kinase C (PKC), enhance synaptic transmission in the CA1 subfield of hippocampus, both in situ and in vitro. The increase in synaptic transmission could be the consequence of enhanced Ca influx into nerve terminals, and perhaps a more general increase in voltage-dependent Ca currents. The effects of phorbol 12,13-diacetate (PDAc) on the high-voltage activated (HVA) Ca currents, as well as spontaneous transient currents were therefore investigated by intracellular recording in hippocampal slices. PDAc selectively augmented, by 45% +/- 10%, the early peak of the HVA Ca current (but not its sustained component), and also spontaneous inhibitory postsynaptic currents. The inactive phorbol ester, 4 alpha-PDAc, had no comparable effects. The actions of PDAc were reversible on prolonged washing, and they were antagonized by the PKC inhibitors (1-(5-isoquinolinesulfonyl)-2-methyl piperazine (H-7) and monosialoganglioside (GM1). In addition, GM1, which also activates the Ca/calmodulin-dependent kinase, enhanced spontaneous excitatory postsynaptic currents, while inhibiting the IPSCs. It is concluded that activation of PKC increases HVA (probably N-type) Ca current and facilitates ongoing GABAergic IPSCs.
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PMID:Modulation of high-threshold Ca current and spontaneous postsynaptic transient currents by phorbol 12,13-diacetate, 1-(5-isoquinolinesulfonyl)-2-methyl piperazine (H-7), and monosialoganglioside (GM1) in CA1 pyramidal neurons of rat hippocampus in vitro. 839 48

1. Three-dimensional spatial patterns of changes in membrane-bound protein kinase C (PKC) were examined in the lumbar spinal cords (L1-L5) of rats with an experimental painful peripheral mononeuropathy. Painful peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, resulting in chronic constrictive nerve injury (CCI). Changes in spinal cord membrane-bound PKC distribution were assayed by employing an established quantitative [3H]-phorbol-12,13-dibutyrate ([3H]PDBu) autoradiographic assay, which includes spinal cord sectioning, incubation of spinal cord sections with [3H]PDBu, production of autoradiographs, and computer-assisted image processing. 2. Sciatic nerve ligation induced demonstrable thermal hyperalgesia in response to radiant heat stimulation and spontaneous pain-related behaviors (such as lifting of the nerve-ligated hind paw) in CCI rats 3, 7, and 10 days after unilateral sciatic nerve ligation. 3. Consistent with behavioral changes, CCI rats examined 3 or 10 days after sciatic nerve ligation displayed a three-dimensional pattern of increased membrane-bound PKC in the lumbar spinal cord (L1-L5) strikingly different from that of sham-operated rats: in the dorsoventral dimension, reliable increases in membrane-bound PKC occurred mainly within spinal cord laminae I-IV and V-VI in CCI rats; in the ipsilateral-contralateral dimension, changes in membrane-bound PKC were seen on both sides of the spinal cord in CCI rats with reliably higher levels of membrane-bound PKC on the side ipsilateral than on the side contralateral to sciatic nerve ligation; in the rostrocaudal dimension, increases in membrane-bound PKC in the spinal cord dorsal horns of CCI rats extended from spinal segments L2-L5. 4. Both three-dimensional increases in spinal cord membrane-bound PKC and nociceptive behaviors (thermal hyperalgesia and spontaneous pain behaviors) in CCI rats were reliably reduced after three daily intrathecal treatments with 80 nmol GM1 ganglioside (a glycosphingolipid shown to prevent PKC translocation/activation), the first of which was given 1 h after sciatic nerve ligation. This reduction was seen 24 h but not 7 days after the last GM1 ganglioside treatment. 5. This three-dimensional increase in membrane-bound PKC in the spinal cord dorsal horn of CCI rats displayed high correlations with thermal hyperalgesia and with spontaneous pain-related behaviors in CCI rats observed both 3 and 10 days after sciatic nerve ligation. Similar correlations were observed between decreases in levels of membrane-bound PKC in the spinal cord dorsal horn and the attenuation of nociceptive behaviors in CCI rats after three daily intrathecal treatments with GM1 ganglioside.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy. 841 Jan 49

A single dose of 0.25 ng of tetanus toxin (TeTx), equivalent to approximately 5 minimal lethal doses, injected intracerebrally to 1-day-old rats, caused translocation, i.e., activation, of Ca(2+)-phosphatidylserine-dependent protein kinase C (PKC) from the cytosolic to the membrane compartment within 1 h. Six hours after treatment with the toxin, a 40-50% reduction in the total brain PKC (cytosolic plus membrane) activity was noticed. GT1b (2 micrograms per brain) ganglioside, a putative receptor for TeTx, completely prevented enzyme translocation when injected intracerebrally 30 min before toxin administration and abolished down-regulation after 6 h from the time of toxin injection. GM1 (2 micrograms per brain), a ganglioside of lesser affinity for TeTx, produced by itself a 20-30% reduction of the total PKC activity and did not reverse TeTx-induced PKC down-regulation after 6 h. 12-O-Tetradecanoylphorbol 13-acetate (TPA) phorbol ester, administered at a concentration of 5 x 10(-5) M, caused activation and down-regulation of the enzyme, although with several orders of magnitude lesser potency. GT1b prevented the TPA-induced down-regulation.
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PMID:GT1b ganglioside prevents tetanus toxin-induced protein kinase C activation and down-regulation in the neonatal brain in vivo. 841 45

Exposure of rat cortical neurons to the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 in vitro causes a rise in the intracellular Ca2+ level and a subsequent translocation of protein kinase C (PKC) from the cytosol to the membrane. Such a translocation persists for at least 2 h, but only in cultures with media not depleted of endogenous glutamate. Enzymatic degradation of glutamate in the medium by the enzyme glutamate-pyruvate transaminase (GPT) abolishes the long-lasting effect of gp120 on the association state of PKC; under this incubation condition the translocation period is < 1 h. Memantine and the ganglioside GM1 prevent N-methyl D-aspartate receptor-mediated long-term translocation of PKC and gp120-mediated neurotoxicity (in the absence of GPT); they have no effect on short-term translocation of PKC. We suggest that gp120-caused neuronal death involves an indirect sensitization step of the NMDA receptors, which ultimately induces neuronal death.
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PMID:HIV-1 gp120 and NMDA induce protein kinase C translocation differentially in rat primary neuronal cultures. 845 39

Sialated glycosphingolipids (gangliosides) were recently shown to induce internalisation of the CD4 Ag in lymphoid cells and dissociation of p56lck from CD4 (Repke et al. (1992) J. Immunol. 149, 2585-2591; Saggioro et al. (1993) J. Biol. Chem. 268, 1368-1375). The findings presented in this paper show that GM1 induces internalisation and the eventual degradation of the CD4 Ag also in the monocytic cell line U937. GM1 effects are independent of a possible activation of protein kinase C, as enzyme inhibitors which effectively blocked phorbol esters effects did not prevent GM1-induced CD4 internalisation and degradation. GM1 effects were also independent of a possible action on a CD4 associated kinase activity as we show that U937 cells lack any CD4-associated kinase activity.
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PMID:The monosialoganglioside GM1 induces internalisation and degradation of the CD4 antigen in U937 cells: evidence for a novel mechanism of CD4 down-modulation in a p56lck-negative cell line, which is independent of protein kinase C activation. 846 87


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