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)

Calexcitin (CE) is a calcium sensor protein that has been implicated in associative learning. The CE gene was previously cloned from the long-finned squid, Loligo pealei, and the gene product was shown to bind GTP and modulate K(+) channels and ryanodine receptors in a Ca(2+)-dependent manner. We cloned a new gene from L. pealei, which encodes a CE-like protein, here named calexcitin B (CE(B)). CE(B) has 95% amino acid identity to the original form. Our sequence analyses indicate that CEs are homologous to the sarcoplasmic calcium-binding protein subfamily of the EF-hand superfamily. Far and near UV circular dichroism and nuclear magnetic resonance studies demonstrate that CE(B) binds Ca(2+) and undergoes a conformational change. CE(B) is phosphorylated by protein kinase C, but not by casein kinase II. CE(B) does not bind GTP. Western blot experiments using polyclonal antibodies generated against CE(B) showed that CE(B) is expressed in the L. pealei optic lobe. Taken together, the neuronal protein CE represents the first example of a Ca(2+) sensor in the sarcoplasmic calcium-binding protein family.
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PMID:Calexcitin B is a new member of the sarcoplasmic calcium-binding protein family. 1130 67

Signaling pathways underlying the cognitive deficit of the Alzheimer's disease (AD) are not completely understood. Protein kinase C (PKC), a major neuronal protein plays a critical role in cellular signal transduction and it is known to be subjected to modulation in AD. We showed previously that, chronic infusion of beta-amyloid (1-40) into rat cerebroventricle leads to deficit in spatial and non-spatial memory formation. As an attempt to identify the cellular correlates of the memory deficit, in the present study we investigated the PKC activation in different brain areas. Chronic infusion of beta-amyloid (1-40) for 14 days into the rat cerebroventricle decreased the activity of soluble protein kinase C (PKC) in the hippocampus. Subcellular translocation of PKC to membrane fraction in hippocampal slices of rats treated with beta-amyloid (1-40) was completely abolished under acute stimulation with 0.5 microM phorbol-dibutyrate (PDBu). We also reported a decreased affinity (k(D)) for PDBu binding in the hippocampus, cerebral cortex and striatum. The total number of binding sites for PDBu (B(max)) was increased, in the three brain areas analyzed on the day 14, but the changes were not statistically significant. Our data indicate that chronic accumulation of beta-amyloid (1-40) into the rat brain reduced activation of PKC, effect that would substantially contribute to the memory deficit found in these animals.
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PMID:Memory impairment induced by chronic intracerebroventricular infusion of beta-amyloid (1-40) involves downregulation of protein kinase C. 1244 70

The observation that natriuretic peptides and protein kinase C activators influence evoked neurotransmitter efflux by diametrically opposed mechanisms prompted an investigation of the influence of natriuretic peptides on protein kinase C activity and the potential involvement of this pathway in neuromodulatory responses to natriuretic peptides. C-Type natriuretic peptide attenuated both evoked dopamine efflux and protein kinase C activity in a concentration-dependent manner consistent with a 10% diminution in protein kinase C activity producing a 4.6-6.2% reduction in evoked dopamine efflux. The ability of C-type natriuretic peptide to suppress evoked dopamine efflux was abolished by treatment with the protein kinase C inhibitors chelerythrine (10 micro M) and staurosporine (10 nM). Both chelerythrine and staurosporine attenuated protein kinase C activity at the concentrations used. The natriuretic peptide C receptor (NPR-C) appeared to mediate the attenuation of protein kinase C activity, because the effect was mimicked by a pentadecapeptide fragment of the NPR-C, and the effect of C-type natriuretic peptide was attenuated by an antibody generated against the same region of the receptor. These data suggest that C-type natriuretic peptide attenuates neurotransmitter efflux by a mechanism involving suppression of neuronal protein kinase C activity via an interaction with the NPR-C.
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PMID:Natriuretic peptides suppress protein kinase C activity to reduce evoked dopamine efflux from pheochromocytoma (PC12) cells. 1248 34

WW domain-containing proteins are found in all eukaryotic cells and they are involved in the regulation of a wide variety of cellular functions. We recently identified the neuronal protein KIBRA as novel member of this family of signal transducers. In this report, we describe the identification of protein kinase C (PKC) zeta as a KIBRA-interacting protein. PKCzeta is known to play an important role in synaptic plasticity and memory formation but its specific targets are not well known. Our studies presented here revealed that KIBRA is a novel substrate for PKCzeta and suggest that PKCzeta phosphorylation may regulate the cellular function of KIBRA.
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PMID:KIBRA is a novel substrate for protein kinase Czeta. 1508 97

Hyperammonemia is responsible for most neurological alterations in patients with hepatic encephalopathy by mechanisms that remain unclear. Hyperammonemia alters phosphorylation of neuronal protein kinase C (PKC) substrates and impairs NMDA receptor-associated signal transduction. The aim of this work was to analyse the effects of hyperammonemia on the amount and intracellular distribution of PKC isoforms and on translocation of each isoform induced by NMDA receptor activation in cerebellar neurons. Chronic hyperammonemia alters differentially the intracellular distribution of PKC isoforms. The amount of all isoforms (except PKC zeta) was reduced (17-50%) in the particulate fraction. The contents of alpha, beta1, and epsilon isoforms decreased similarly in cytosol (65-78%) and membranes (66-83%), whereas gamma, delta, and theta; isoforms increased in cytosol but decreased in membranes, and zeta isoform increased in membranes and decreased in cytosol. Chronic hyperammonemia also affects differentially NMDA-induced translocation of PKC isoforms. NMDA-induced translocation of PKC alpha and beta is prevented by ammonia, whereas PKC gamma, delta, epsilon, or theta; translocation is not affected. Inhibition of phospholipase C did not affect PKC alpha translocation but reduced significantly PKC gamma translocation, indicating that NMDA-induced translocation of PKC alpha is mediated by Ca2+, whereas PKC gamma translocation is mediated by diacylglycerol. Chronic hyperammonemia reduces Ca+2-mediated but not diacylglycerol-mediated translocation of PKC isoforms induced by NMDA.
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PMID:Chronic exposure to ammonia induces isoform-selective alterations in the intracellular distribution and NMDA receptor-mediated translocation of protein kinase C in cerebellar neurons in culture. 1560 4

Neurogranin/RC3 (Ng/rodent cortex-enriched mRNA clone #3), a postsynaptic neuronal protein kinase C (PKC) substrate, binds calmodulin (CaM) at low Ca(2+) levels. Neurotransmitters triggering influx calcium induce neurogranin phosphorylation by PKC in physiological or pathophysiological conditions. Phosphorylated Ng reduces the affinity of Ng to bind CaM, which may affect the activities of calmodulin-dependent downstream enzymes, such as nitric oxide synthase (NOS), CaM-dependent protein kinase II (CaMKII) and adenylate cyclase (AC). These protein enzymes have been reported to play key roles in the development of ischemic/hypoxic preconditioning (I/HPC). We previously demonstrated that activation of cPKCbetaII and gamma isoforms may be involved in the early phase of cerebral hypoxic preconditioning. However, as a substrate of PKC, the role of Ng in the onset of cerebral hypoxic preconditioning is unknown. In this study, we examined the effects of repetitive hypoxic exposure on the status of Ng phosphorylation in the cortex and hippocampus of mice. Using Western blot analysis, we found that the levels of Ng phosphorylation in the cortex and hippocampus of the hypoxic group of mice increased significantly from that of the normoxic group (p<0.05). These results suggest that neurogranin protein may be involved in the development of cerebral hypoxic preconditioning.
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PMID:Increased phosphorylation of neurogranin in the brain of hypoxic preconditioned mice. 1618 46

The mechanism of specific proteolysis of the neuronal protein GAP-43 in axonal terminals has been investigated. In synaptic terminals in vivo and in synaptosomes in vitro GAP-43 is cleaved only at the single peptide bond formed by Ser41; this is within the main effector domain of GAP-43. Proteolysis at this site involves the cysteine calcium-dependent neutral protease calpain. The following experimental evidences support this conclusion: 1) calcium-dependent proteolysis of GAP-43 in synaptosomes is insensitive to selective inhibitor of micro-calpain (PD151746), but it is completely blocked by micro- and m-calpain inhibitor PD150606; 2) GAP-43 proteolysis in the calcium ionophore A23187-treated synaptosomes is activated by millimolar concentration of calcium ions; 3) the pattern of fragmentation of purified GAP-43 by m-calpain (but not by micro-calpain) is identical to that observed in synaptic terminals in vivo. GAP-43 phosphorylated at Ser41 by protein kinase C (PKC) is resistant to the cleavage by calpain. In addition, calmodulin binding to GAP-43 decreases the rate of calpain-mediated GAP-43 proteolysis. Our results indicate that m-calpain-mediated GAP-43 proteolysis regulated by PKC and calmodulin is of physiological relevance, particularly in axonal growth cone guidance. We suggest that the function of the N-terminal fragment of GAP-43 (residues 1-40) formed during cleavage by m-calpain consists in activation of neuronal heterotrimeric GTP-binding protein G(o); this results in growth cone turning in response to repulsive signals.
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PMID:Specific proteolysis of neuronal protein GAP-43 by calpain: characterization, regulation, and physiological role. 1621 46

Enhancement of AMPA receptor activity in response to synaptic plasticity inducing stimuli may arise, in part, through phosphorylation of the GluR1 AMPA receptor subunit at Ser-831. This site is a substrate for both Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). However, neuronal protein levels of CaMKII may exceed those of PKC by an order of magnitude. Thus, it is unclear how PKC could effectively regulate this common target site. The multivalent neuronal scaffold A-kinase-anchoring protein 79 (AKAP79) is known to bind PKC and is linked to GluR1 by synapse-associated protein 97 (SAP97). Here, biochemical studies demonstrate that AKAP79 localizes PKC activity near the receptor, thus accelerating Ser-831 phosphorylation. Complementary electrophysiological studies indicate that AKAP79 selectively shifts the dose-dependence for PKC modulation of GluR1 receptor currents approximately 20-fold, such that low concentrations of PKC are as effective as much higher CaMKII concentrations. By boosting PKC activity near a target substrate, AKAP79 provides a mechanism to overcome limitations in kinase abundance thereby ensuring faithful signal propagation and efficient modification of AMPA receptor-mediated responses.
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PMID:AKAP79 selectively enhances protein kinase C regulation of GluR1 at a Ca2+-calmodulin-dependent protein kinase II/protein kinase C site. 1830 16

In this study, we have used the PC12 cell model to elucidate the mechanisms by which sublethal doses of oxidants induce neuritogenesis. The xanthine/xanthine oxidase (X/XO) system was used for the steady state generation of superoxide, and CoCl(2) was used as a representative transition metal redox catalyst. Upon treatment of purified protein kinase C (PKC) with these oxidants, there was an increase in its cofactor-independent activation. Redox-active cobalt competed with the redoxinert zinc present in the zinc-thiolates of the PKC regulatory domain and induced the oxidation of these cysteine-rich regions. Both CoCl(2) and X/XO induced neurite outgrowth in PC12 cells, as determined by an overexpression of neuronal marker genes. Furthermore, these oxidants induced a translocation of PKC from cytosol to membrane and subsequent conversion of PKC to a cofactor-independent form. Isoenzyme-specific PKC inhibitors demonstrated that PKCepsilon plays a crucial role in neuritogenesis. Moreover, oxidant-induced neurite outgrowth was increased with a conditional overexpression of PKCepsilon and decreased with its knock-out by small interfering RNA. Parallel with PKC activation, an increase in phosphorylation of the growth-associated neuronal protein GAP-43 at Ser(41) was observed. Additionally, there was a sustained activation of extracellular signal-regulated kinases 1 and 2, which was correlated with activating phosphorylation (Ser(133)) of cAMP-responsive element-binding protein. All of these signaling events that are causally linked to neuritogenesis were blocked by antioxidant N-acetylcysteine (both L and D-forms) and by a variety of PKC-specific inhibitors. Taken together, these results strongly suggest that sublethal doses of oxidants induce neuritogenesis via a direct redox activation of PKCepsilon.
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PMID:A direct redox regulation of protein kinase C isoenzymes mediates oxidant-induced neuritogenesis in PC12 cells. 1837 50

Protein kinase C (PKC) is involved in synaptic remodeling, induction of protein synthesis, and many other processes important in learning and memory. Activation of neuronal protein kinase C correlates with, and may be essential for, all phases of learning, including acquisition, consolidation, and reconsolidation. Protein kinase C activation is closely tied to hydrolysis of membrane lipids. Phospholipases C and A2 produce 1,2-diacylglycerol and arachidonic acid, which are direct activators of protein kinase C. Phospholipase C also produces inositol triphosphate, which releases calcium from internal stores. Protein kinase C interacts with many of the same pathways as insulin; therefore, it should not be surprising that insulin signaling and protein kinase C activation can both have powerful effects on memory storage and synaptic remodeling. However, investigating the possible roles of insulin in memory storage can be challenging, due to the powerful peripheral effects of insulin on glucose and the low concentration of insulin in the brain. Although peripheral for insulin, synthesized in the beta-cells of the pancreas, is primarily involved in regulating glucose, small amounts of insulin are also present in the brain. The functions of this brain insulin are inadequately understood. Protein kinase C may also contribute to insulin resistance by phosphorylating the insulin receptor substrates required for insulin signaling. Insulin is also responsible insulin-long term depression, a type of synaptic plasticity that is also dependent on protein kinase C. However, insulin can also activate PKC signaling pathways via PLC gamma, Erk 1/2 MAP kinase, and src stimulation. Taken together, the available evidence suggests that the major impact of protein kinase C and its interaction with insulin in the mature, fully differentiated nervous system appears to be to induce synaptogenesis, enhance memory, reduce Alzheimer's pathophysiology, and stimulate neurorepair.
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PMID:Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. 1840 35


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