EC:2.7.11.13 - FACTA Search

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)

Microinjection of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) into Xenopus oocytes evokes a complex physiological response composed of a transient and a slow depolarizing chloride current. We investigated the relationship between intracellular levels of Ins(1,4,5)P3 and the kinetics of the physiological response. Microinjected Ins(1,4,5)P3 was slowly degraded following first order kinetics of disappearance (t1/2 = 10 min). The degradation products were inositol bisphosphate (InsP2), inositol monophosphate (InsP) and inositol, as well as inositol tetrakisphosphate (InsP4). The rate of degradation of injected 3[H]-Ins(1,4)P2 was much greater (t1/2 = 3 min), indicating that the conversion of InsP3 to InsP2 may be the rate-limiting step in the degradation process. The slow degradation of 3[H]-Ins(1,4,5)P3 was not a result of its conversion to Ins(1,3,4)P3 since no accumulation of InsP3 was observed within 10 min of microinjection of 3[H]-Ins(1,3,4,5)P4. Activation of protein kinase C (PK-C) with a phorbol ester transiently increased the rate of conversion of 3[H]-Ins(1,4,5)P3 to InsP2. This, however, did not significantly affect the overall kinetics of 3[H]-Ins(1,4,5)P3 disappearance. Our results indicate that the kinetics of Ins(1,4,5)P3 degradation do not correlate well with the termination of both the rapid and the slow components of the physiological response. The termination of the slow component of the response, however, may be related to the decay of Ins(1,4,5)P3-induced 45Ca efflux, which lasted about 10 min.
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PMID:The metabolism of microinjected inositol trisphosphate in Xenopus oocytes. 129 70

Inositol 1,4,5-trisphosphate (IP3) releases internal stores of calcium by binding to a specific membrane receptor which includes both the IP3 recognition site as well as the associated calcium channel. The IP3 receptor is regulated by ATP, calcium, and phosphorylation by protein kinase A, protein kinase C, and calcium/calmodulin-dependent protein kinase II. Its cDNA sequence predicts at least two consensus sequences where nucleotides might bind, and direct binding of ATP to the IP3 receptor has been demonstrated. In the present study, we demonstrate autophosphorylation of the purified and reconstituted IP3 receptor on serine and find serine protein kinase activity of the IP3 receptor toward a specific peptide substrate. Several independent purification procedures do not separate the IP3 receptor protein from the phosphorylating activity, and many different protein kinase activators and inhibitors do not identify protein kinases as contaminants. Also, renaturation experiments reveal autophosphorylation of the monomeric receptor on polyvinylidene difluoride membranes.
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PMID:Autophosphorylation of inositol 1,4,5-trisphosphate receptors. 131 30

There is increasing evidence that endothelial cells respond to a variety of mediators. In the current studies rat pulmonary artery endothelial cells (RPAEC) responded to human recombinant C5a and tumor necrosis factor-alpha (TNF-alpha) with the generation of superoxide (O2-). RPAEC responsiveness was dependent on whether cells had been obtained from confluent or subconfluent cell monolayers. RPAEC responded to C5a and TNF-alpha in a dose-dependent manner, with increases in intracellular Ca2+ (Cai2+), formation of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], and generation of O2-. Optimal O2- responses occurred in cells that had been pretreated with the inhibitor of superoxide dismutase (SOD), diethyldithiocarbamate, and O2- responses were allopurinol insensitive. Pertussis toxin pretreatment abolished the ability of C5a to cause increases in Ins(1,4,5)P3 and Cai2+ and formation of O2- but did not inhibit the changes in Cai2+ and formation of O2- after addition of TNF-alpha. The O2- response to C5a but not to TNF-alpha was abolished by pretreatment with the inhibitor of protein kinase C, staurosporine. These data indicate that signal transduction events in response to C5a and TNF-alpha were fundamentally different.
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PMID:Superoxide responses of endothelial cells to C5a and TNF-alpha: divergent signal transduction pathways. 132 51

We measured the masses of inositol 1,4,5 trisphosphate (Ins(1,4,5)P3) and diacylglycerol (DAG) in hepatocytes in response to both epidermal growth factor (EGF) and vasopressin. EGF at 25 nM did not alter Ins(1,4,5)P3 content of hepatocytes. However, the combination of 100 nM EGF concentration and incubation with lithium did increase Ins(1,4,5)P3 content. This increase was only one tenth of that elicited by vasopressin in parallel incubations. This finding resolves a controversy concerning the ability of EGF to increase Ins(1,4,5)P3 in hepatocytes, and argues against a role for phosphoinositide hydrolysis in EGF action in hepatocytes. Both EGF and vasopressin caused a rapid (30 s) increase in DAG content. A delayed increase in DAG content, that was maximal after several minutes, was observed only for vasopressin. The rapid increase in DAG content implies an activation of protein kinase C for both EGF and vasopressin.
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PMID:Effects of EGF on the mass of inositol 1,4,5-trisphosphate and SN(1,2)-diacylglycerol in freshly isolated rat hepatocytes: comparison with vasopressin. 132 47

Hepatocytes respond to stimulation by glycogenolytic agonists acting via phosphoinositide (PI) breakdown through oscillations of the free cytosolic concentration of Ca2+ ([Ca2+]cyt.). Since the second-messenger repertoire of hepatocytes includes many other factors besides Ca2+, we investigated to what degree the regulation of [Ca2+]cyt. oscillations is integrated into these other signalling systems. [Ca2+]cyt. was recorded in single rat hepatocytes by using the Ca(2+)-indicator fura-2. Parallel stimulation with phenylephrine (an alpha 1-adrenergic agonist of PI breakdown) and glucagon resulted in a synergistic stimulation of [Ca2+]cyt. oscillations. Direct activation of the cyclic-AMP-dependent pathway with several stimuli (forskolin, 8-bromo cyclic AMP, 8-CPT cyclic AMP) mimicked the response to glucagon. In contrast, [Ca2+]cyt. oscillations induced by various combinations of these agonists could be antagonized by the glycogenic hormone insulin. As one of the options in the insulin-signalling network, we tested a diacylglycerol activator of protein kinase C, DiC8. It also acted as an inhibitor of [Ca2+]cyt. oscillations. We investigated how these observations could be reconciled with our previously introduced model of [Ca2+]cyt. oscillations in hepatocytes [Somogyi and Stucki (1991) J. Biol. Chem. 266, 11068-11077]. First of all, the effect of calmodulin inhibitors (calmidazolium and CGS 9343 B), acting at the core of our model on the feedback of Ca2+ on Ins(1,4,5)P3-induced Ca2+ release, was not altered by the new modulators. In addition, all agonists and antagonists could be used interchangeably in combination and introduced no significant change in the oscillatory pattern or spike shape. Since the response was solely limited to frequency modulation, over- or understimulation of the oscillatory system, there is no need to create a new oscillator or to introduce further reaction steps into the core of the model. We conclude that the regulation of [Ca2+]cyt. via the explored second-messenger pathways can be embedded into the oscillatory system as modulation of rate constants already present in this model.
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PMID:Modulation of cytosolic-[Ca2+] oscillations in hepatocytes results from cross-talk among second messengers. The synergism between the alpha 1-adrenergic response, glucagon and cyclic AMP, and their antagonism by insulin and diacylglycerol manifest themselves in the control of the cytosolic-[Ca2+] oscillations. 132 20

1. The characteristics of vasopressin-stimulated phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) and phosphatidylcholine (PtdCh) hydrolysis were examined in A10 vascular smooth muscle cells (VSMC), by assessing the formation of [3H]-inositol phosphates ([3H]-IP) and the accumulation of the phospholipase D (PLD) specific product, [3H]-phosphatidylbutanol ([3H]-PtdBuOH). 2. Vasopressin ([Arg8]-VP) and a number of related analogues stimulated the accumulation of [3H]-IP and [3H]-PtdBuOH with similar EC50 values, generating the same rank order of potency for each response (Arg8-VP = vasotocin = Lys8-VP much greater than oxytocin). 3. Inhibition of vasopressin-stimulated [3H]-IP and [3H]-PtdBuOH accumulation by the V1a receptor antagonists, Des-Gly9[beta-mercapto-beta,beta,-cyclopentamethylene propionyl, O-Et-Tyr2,Val4,Arg8]-vasopressin generated similar IC50 values suggesting that both these responses are mediated through the activation of a single V1a receptor subtype. 4. The onset of vasopressin-stimulated inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) mass formation preceded [3H]-PtdBuOH accumulation indicating that PtdCh hydrolysis was activated subsequent to PtdIns(4,5)P2 breakdown. 5. The protein kinase C (PKC) activator, tetradecanoylphorbol acetate (TPA) also stimulated [3H]-PtdBuOH accumulation. Preincubation with the PKC inhibitor Ro-31-8220 abolished both TPA- and vasopressin-stimulated [3H]-PtdBuOH, suggesting that the intermediate activation of protein kinase C is involved in the regulation of PLD by vasopressin. 6. Pretreatment of the A10 VSMC with Ro-31-8220 (100 microM) also potentiated vasopressin-stimulated Ins(1,4,5)P3 mass formation.Therefore stimulation of PKC may have opposing roles in the regulation of agonist activation of PLC and PLD.7. Preincubation of the cells with EGTA, verapamil, or the receptor-operated calcium channel antagonist, SK&F 96365, reduced vasopressin-stimulated [3H]-PtdBuOH accumulation by approximately 30%, suggesting that influx of calcium has a significant role to play in the regulation of vasopressinstimulated PLD activity.
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PMID:Vasopressin-stimulated [3H]-inositol phosphate and [3H]-phosphatidylbutanol accumulation in A10 vascular smooth muscle cells. 133 Jan 54

We examined the effects of heparin, guanosine nucleotides, protein kinase C (PKC) modulators, such as phorbol 12,13-dibutyrate (PDBu) and H-7 on Ca(2+)-dependent K+ currents in smooth muscle cells of the rabbit portal vein using the whole-cell patch-clamp technique, to explore the effects of PKC on the oscillatory outward current (Ioo). Neomycin (30 microM), an inhibitor of phospholipase C, and intracellular applications of heparin (10 micrograms/ml) and guanosine 5'-O-(2-thiodiphosphate) (GDP[beta S]; 1 mM) partly but consistently inhibited the generation of Ioo, whereas a higher concentration of heparin (100 micrograms/ml) transiently enhanced then suppressed the generation of Ioo. Inhibition of Ioo generation by heparin was more powerful at the holding potential of +20 mV than at -20 mV. Inositol 1,4,5-trisphosphate (InsP3; 30 microM) continuously generated Ioo at holding potentials more positive than -60 mV. Noradrenaline (10 microM) and caffeine (3-20 mM) transiently augmented, then reduced the generation of Ioo. Heparin (10 micrograms/ml) completely inhibited responses induced by InsP3 and noradrenaline, but not those induced by caffeine. Intracellular application of guanosine 5'-triphosphate (GTP; 200 microM) or low concentrations of guanosine 5'-O-(3-thiotriphosphate) (GTP[gamma S]; < or = 3 microM) continuously augmented the generation of Ioo. High concentrations of GTP[gamma S] (> or = 10 microM) transiently augmented, then inhibited Ioo. Neither GTP[gamma S] nor noradrenaline induced the transient augmentation or the subsequent inhibition of Ioo when applied in the presence of GDP[beta S] (1 mM), neomycin (30 microM) or heparin (10 micrograms/ml). PDBu (0.1 microM) reduced the generation of Ioo but failed to produce an outward current following application of caffeine (3-5 mM). This action of PDBu was inhibited by pretreatment with H-7 (20 microM). In the presence of H-7, GTP[gamma S] continuously enhanced the generation of Ioo. The suppression of the generation of Ioo during application of noradrenaline (10 microM) was reduced by pretreatment with H-7. Thus both InsP3 and protein kinase C contribute to the generation of Ioo in smooth muscle cells of the rabbit portal vein and heparin is not a specific InsP3 antagonist on the InsP3-induced Ca(2+)-release channel (PIRC). InsP3 opens PIRC and protein kinase C may deplete the stored Ca2+ by either inhibiting the reuptake of Ca2+ or by enhancement of the releasing actions of InsP3.
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PMID:Roles of inositol trisphosphate and protein kinase C in the spontaneous outward current modulated by calcium release in rabbit portal vein. 133 73

The tyrosine kinase inhibitors ST271, ST638 and erbstatin inhibited phospholipase D (PLD) activity in human neutrophils stimulated by fMet-Leu-Phe, platelet-activating factor and leukotriene B4. These compounds did not inhibit phorbol ester-stimulated PLD, indicating that they do not inhibit PLD per se, but probably act at a site between the receptor and the phospholipase. In contrast, the protein kinase C inhibitor Ro-31-8220 inhibited phorbol 12,13-dibutyrate- but not fMet-Leu-Phe-stimulated PLD activity, arguing against the involvement of protein kinase C in the receptor-mediated activation of PLD. ST271 did not inhibit Ins(1,4,5)P3 generation, but did inhibit protein tyrosine phosphorylation stimulated by fMet-Leu-Phe. The phosphotyrosine phosphatase inhibitor pervanadate increased tyrosine phosphorylation and stimulated PLD. These results suggest that tyrosine kinase activity is involved in receptor coupling to PLD but not to PtdIns(4,5)P2-specific phospholipase C in the human neutrophil.
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PMID:Tyrosine phosphorylation is involved in receptor coupling to phospholipase D but not phospholipase C in the human neutrophil. 137 83

Stimulation of [3H]inositol-prelabelled rat cerebral-cortex slices with carbachol results in the accumulation of four [3H]inositol bisphosphate isomeric species, Ins(1,3)P2, Ins(1,4)P2, Ins(3,4)P2 and Ins(4,5)P2. Although the last isomer ran as a minor peak on h.p.l.c., its accumulation was dramatically enhanced in the presence of Li+ (1 mM), such that at 30 min it represented almost 35% of the total bisphosphate fraction. The accumulation of Ins(4,5)P2 appeared to be very sensitive to Li+ (EC50 = 94 +/- 3 microM), strongly implicating a Li(+)-sensitive metabolism. Evidence for this is provided from the rapid but Li(+)-sensitive decay of Ins(4,5)P2 when muscarinic-receptor stimulation is antagonized by atropine at a time when accumulations have reached a new steady state. Manipulation of phospholipase D by activators and inhibitors of protein kinase C did not suggest a role for phospholipase D hydrolysis of PtdInsP2 in the formation of Ins(4,5)P2. Attempts to reveal Ins(4,5)P2 metabolism, or indeed its synthesis from Ins(1,4,5)P3, were not successful with broken cell preparations and strongly suggest discrete compartmentation of inositol phosphate metabolism in the intact cell.
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PMID:Evidence for lithium-sensitive inositol 4,5-bisphosphate accumulation in muscarinic cholinoceptor-stimulated cerebral-cortex slices. 144 2

1. The possibility that bradykinin- or histamine-stimulated inositol polyphosphate accumulation may be regulated by protein kinase C (PKC) in bovine adrenal chromaffin cells has been addressed. 2. Initial experiments confirmed that the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) dramatically inhibited agonist-stimulated [3H]-inositol phosphate accumulations in [3H]-inositol prelabelled cells. In contrast, the PKC inhibitor, Ro 31-8220, did not affect this response. 3. Histamine (100 microM) or bradykinin (100 nM) evoked rapid increases in inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) mass accumulations (maximal accumulations within 10 s and 30 s, respectively) which declined towards basal values over a 10 min incubation period. TPA (1 microM) significantly attenuated the peak Ins(1,4,5)P3 response to bradykinin and histamine by 30% and 70% respectively. In contrast, TPA did not significantly affect agonist-stimulated Ins(1,3,4,5)P4 responses. 4. Ro 31-8220 (10 microM) significantly enhanced the maximal Ins(1,4,5)P3 accumulations elicited by both bradykinin and histamine. 5. The results indicate that the initial Ins(1,4,5)P3 response to either bradykinin or histamine in bovine adrenal chromaffin cells can be attenuated by PKC activation by phorbol ester and enhanced by PKC inhibition by Ro 31-8220. In contrast, agonist-stimulated Ins(1,3,4,5)P4 accumulation does not appear to be affected by these manipulations of PKC activity. Possible bases for differential modulation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 are discussed.
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PMID:Role of protein kinase C in the regulation of histamine and bradykinin stimulated inositol polyphosphate turnover in adrenal chromaffin cells. 146 36

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