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 have demonstrated that NMDA receptor antagonists and protein kinase C inhibitors induced marked memory impairment in rats, but that peripherally administered cerulein (CER) prevented these effects. In the present study, the effect of subcutaneously administered CER on amnesia induced by protein synthesis inhibitors was examined in passive and active avoidance responses and in the Morris water maze test. Intraperitoneal injection of the inhibitors produced marked memory impairment, but the effect was abolished by combined administration with CER. The effective dose of subcutaneously injected CER was, on a molar basis, three thousand- and six thousandfold less than the dose of anisomycin, and two hundred eighty- and three thousandfold less than the dose of puromycin in the passive and active avoidance response experiments, respectively. Similarly, in the Morris water maze test, behavioral disturbances produced by the protein synthesis inhibitors were abolished by CER. These results indicate the effectiveness of CER in preventing memory impairment induced by protein synthesis inhibitors.
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PMID:Protective effect of cerulein on memory impairment induced by protein synthesis inhibitors in rats. 148 May 6

In primary cultures of neurons from rat cerebral cortex and neostriatum, excitatory amino acids stimulate the translocation of protein kinase C (PKC) from the cytoplasm to the membrane. In the presence of a physiological concentration of Mg2+ in the extracellular medium, glutamate induces PKC translocation by binding to both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) excitatory amino acid receptors. Quisqualate translocates the enzyme by stimulating primarily AMPA receptors and possibly metabotropic receptors. NMDA receptor-induced PKC translocation is sodium independent, whereas quisqualate receptor-induced PKC translocation is sodium dependent; none of the agonists is active in the absence of calcium from the extracellular medium. Muscimol does not modify excitatory amino acid stimulation; however, blockade of gamma-aminobutyric acid(A) receptors by bicuculline greatly enhances glutamate-induced PKC translocation. This enhancement is blocked by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) and by tetrodotoxin.
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PMID:Modulation of protein kinase C translocation by excitatory and inhibitory amino acids in primary cultures of neurons. 164 49

Among the various molecular events that have been proposed to contribute to the mechanisms of long-term potentiation (LTP), one of the most cited possibilities has been the activation of protein kinase C (PKC). Here we review various aspects of the cellular actions of PKC activation and inhibition, with special emphasis on the effects of the kinase on synaptic transmission and the N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated components of synaptic responses. We discuss the implications of these effects for interpretations of the role of PKC in the mechanisms of LTP induction and maintenance.
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PMID:Long-term potentiation, protein kinase C, and glutamate receptors. 166 89

Vestibular compensation is the process of behavioral recovery that occurs following unilateral deafferentation of the vestibular nerve fibers (unilateral labyrinthectomy, UL). Since UL results in a permanent loss of vestibular input from the ipsilateral vestibular (VIIIth) nerve, vestibular compensation is attributed to CNS plasticity and has been used as a general model of lesion-induced CNS plasticity. Behavioral recovery from the ocular motor and postural symptoms of UL is correlated with a partial return of resting activity to neurons in the vestibular nucleus (VN) on the deafferented side (the "deafferented VN"), and lesions to the deafferented VN prevent compensation; therefore, the regeneration of resting activity within the deafferented VN is believed to have a causal role in vestibular compensation. The biochemical mechanisms responsible for the adaptive neuronal changes within the deafferented VN are poorly understood. Neuropeptide hormone fragments, such as adrenocorticotrophic hormone (ACTH)-4-10, have been shown to accelerate vestibular compensation and can act directly on some VN neurons in vitro. Antagonists for the N-methyl-D-aspartate (NMDA) receptor have been shown to inhibit vestibular compensation if administered early in the compensation process. Biochemical studies in frog indicate marked alterations in the phosphorylation patterns of several proteins during compensation, and the in vitro phosphorylation of some of these proteins is modulated by ACTH-(1-24), calcium (Ca2+), and calmodulin or protein kinase C. It is therefore possible that ACTH fragments and NMDA antagonists (via their effects on NMDA receptor-mediated Ca2+ channels) modulate vestibular compensation through their action on Ca(2+)-dependent pathways within VN neurons. Recent studies have shown that some Ca2+ channel antagonists and the Ca(2+)-dependent enzyme inhibitor calmidazolium chloride facilitate vestibular compensation. How the regulation of Ca2+ may be related to the neuronal changes responsible for vestibular compensation is unclear at present.
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PMID:Molecular mechanisms of brainstem plasticity. The vestibular compensation model. 166 92

The effects of the phorbol ester 4 beta-phorbol-12,13 dibutyrate (PDBu) and the protein kinase (PK) inhibitors H-7 and sphingosine were investigated on the short-term potentiation (STP) of the population excitatory postsynaptic potential (EPSP) induced by perfusion of N-methyl-D-aspartate (NMDA) in the stratum radiatum of CA1 of the rat hippocampal slice. Bath perfusion of 130 microM NMDA for 10 s caused an initial depression of the population EPSP followed by a STP, which averaged 46% and lasted 16 min. PDBu (100 nM) perfused for 2 h completely inhibited the NMDA induced STP, suggesting that the stimulation of PKC inhibited an NMDA receptor activated process which induced the STP. The protein kinase inhibitors H-7 and sphingosine did not alter the NMDA induced STP.
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PMID:Inhibition of an N-methyl-D-aspartate induced short-term potentiation in the rat hippocampal slice. 177 45

The effects of phospholipase blockers on tetanus-induced long-term potentiation (LTP) and of diacylglycerol (DG) and arachidonic acid (AA) on synaptic transmission were studied in CA1 neurons of guinea pig hippocampal slices to evaluate the role of protein kinase C (PKC) and AA on the maintenance of LTP. Tetanus-induced LTP was suppressed by perfusion with neomycin (1 mM) or 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC, 0.1 mM), blockers of phospholipase. 1-Oleoyl-2-acetyl-glycerol (OAG, 100 micrograms/ml) and AA (100 microM) produced a temporal increase in both the amplitude of the population spike (PS) and the slope of the field excitatory postsynaptic potentials (EPSPs) but failed to produce LTP. Application of OAG or AA in low-Mg2+ (0.1 mM) solution induced LTP. OAG- and AA-induced LTP was blocked by DL-2-amino-phosphopentanoic acid (AP5; 50 microM). The administration of a potent activator of PKC, phorbol-12,13-dibutyrate (PDBu), in low-Mg2+ (0.1 mM) solution enhanced the PS and EPSPs for 2 or 3 h but this enhancement did not persist. These results suggest that PKC activation is not as important as AA for the maintenance of LTP and that OAG and AA play important roles in the maintenance of LTP in synergy with the influx of Ca2+ through NMDA receptor-coupled channels.
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PMID:Both arachidonic acid and 1-oleoyl-2-acetyl glycerol in low magnesium solution induce long-term potentiation in hippocampal CA1 neurons in vitro. 178 53

Ependymin, a glycoprotein of the brain ECF, has been implicated in the neurochemistry of memory and neuronal regeneration. Three behavioral experiments (swimming with a float, avoidance conditioning, and classical conditioning) in the goldfish and one in the mouse (T-maze learning) indicate that ependymin has a role in the synaptic changes that take place in the consolidation step of memory formation and the activity-dependent phase of sharpening of goldfish retinotectal connections during neuronal regeneration. The ECF concentration of the protein was found to decrease after the goldfish learned to associate a light stimulus (CS) with the subsequent arrival of a shock (US): paired CS-US gave changes whereas an unpaired presentation of CS-US gave no changes relative to the unstimulated controls. Ependymin is present in ECF as a mixture of three disulfide-linked dimers of two acidic (alpha and beta) polypeptide chains (37 kDa and 31 kDa). Upon removal of its N-linked glycan fragment by N-glycosidase F, the beta chain yields gamma-ependymin (26 kDa). Determinations of the amino acid sequence of gamma-ependymin indicate that it is a unique protein with no long sequence homologies to any known polypeptide. There are, however, small segments (5-7 amino acids long) with homologies to fibronectin, laminin, and tubulin. Ependymin has the capacity to polymerize into FIP (after activation by phosphorylation) in response to events that deplete ECF calcium. FIP is insoluble in 2% SDS in 6 M urea, 10 mM Ca2+Ac2, 100% acetic acid, chloroform/methanol (2/1), saturated KCNS, and even 100% trifluoroacetic acid. FIP was found to be present in goldfish brain and to be formed as a labeled product in vivo. Ependymin's FIP-forming property was used to propose a molecular hypothesis for generating synaptic changes in response to local extracellular depletions of calcium at sites of "associating inputs." The model assumes that, following NMDA receptor stimulation, the translocated PKC that is generated activates extracellular ependymin by converting it to its phosphorylated form using presynaptically released ATP. The hypothesis was tested in studies of LTP of rat hippocampal slices at CA1. After LTP, new sites that stained with antisera to ependymin, visible at 100x, were obtained in its potentiated radiatum in the CA1 region but not in the unpotentiated CA3. Electron microscopic studies showed that the horseradish peroxidase reaction product obtained was localized at synaptic clefts and postsynaptic regions. The results suggest that FIP may be formed at extracellular and postsynaptic loci where multiple associating inputs interact at CA1.
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PMID:Ependymin, a brain extracellular glycoprotein, and CNS plasticity. 183 64

N-methyl-D-aspartate (NMDA)-induced translocation of protein kinase C from the cytosol to membrane fractions was examined by the [3H]phorbol 12,13-dibutyrate (PDBu) binding method in guinea pig cerebral synaptoneurosomes. Pretreatment of synaptoneurosomes with NMDA, but not that with quisqualate or kainate, induced changes in the distribution of [3H]PDBu binding in the cytosol and membrane fractions in a dose-dependent manner. The NMDA-induced changes of the binding were completely dependent on Ca2+ and inhibited by NMDA receptor antagonists Mg2+, 2-amino-5-phosphonovaleric acid and ketamine, but not by Zn2+. Glycine slightly potentiated the NMDA-induced changes of [3H]PDBu binding. NMDA stimulated Ca2+ uptake but not the phosphoinositide hydrolysis in the synaptoneurosomes. These results suggest that NMDA enhances Ca2+ influx through receptor-operated Ca2+ channels, increasing intracellular calcium concentration and thereby induces translocation of protein kinase C.
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PMID:NMDA induces protein kinase C translocation in guinea pig cerebral synaptoneurosomes. 189 75

N-Methyl-D-aspartate (NMDA)-induced translocation of protein kinase C (PKC) from cytosol to membrane fractions was examined by the methods of [3H]phorbol 12,13-dibutyrate binding and western blotting in rat hippocampal slices. NMDA and L-glutamate induced translocation of PKC from cytosol to membrane fractions in immature rat hippocampal slices, but not in mature ones. The NMDA-induced translocation of PKC was dependent on Ca2+. It was inhibited by the NMDA receptor antagonists, 2-amino-5-phosphonovaleric acid and ketamine, but not by Mg2+ and Zn2+. These results suggest that stimulation of NMDA receptors enhances Ca2+ influx and thereby induces translocation of PKC in immature rat hippocampus.
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PMID:NMDA induces protein kinase C translocation in hippocampal slices of immature rat brain. 192 21

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.
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PMID:Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium. 214 19


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