Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the intracellular free calcium ([Ca2+]i) of cultured normal human epidermal keratinocytes (NHEK) were investigated in order to determine whether the adenylate cyclase cAMP (AC) system and phospholipase C activating system are involved in increasing [Ca2+]i. NHEK were obtained from neonatal foreskin and grown in serum-free medium (K-GM) supplemented with 2% bovine pituitary extract. [Ca2+]i was measured by fluorescence ratio imaging microscopy using Fura-2 as the indicator. In the case of the AC system, transient increases in [Ca2+]i were observed in response to stimulation with epinephrine, norepinephrine, isoproterenol and salbutamol. Methoxamine, clonidine and dobutamine did not induce any [Ca2+]i increase. The [Ca2+]i increase evoked by epinephrine was inhibited by pretreatment with propranolol, but not by prazosin or yohimbine, indicating that epinephrine-induced [Ca2+]i elevation via beta 2-adrenergic stimulation. Similar changes were observed when NHEK were stimulated with histamine, adenosine, GTP gamma S, forskolin and dibutyryl cAMP respectively. The absence of extracellular Ca2+ had no effect on the epinephrine-induced [Ca2+]i increase. It appears that activated protein kinase A, based on cAMP accumulation via stimulatory GTP binding protein, elicited the release of Ca2+ from intracellular stores. On the other hand, when drugs known to activate phospholipase C in a wide variety of cell types were tested, a transient increase in [Ca2+]i was demonstrated in response to the addition of thrombin, bradykinin and substance P. This reaction was not affected by the presence of EGTA, suggesting that these drugs raise [Ca2+]i via phosphatidylinositol breakdown. Vasopressin, angiotensin II, serotonin and acetylcholine did not induce any increase in [Ca2+]i. On the basis of these studies, it was concluded that NHEK possess the mechanism which increase [Ca2+]i via AC system and phospholipase C activating system. It seems probable that this rise in [Ca2+]i initiates a calcium-dependent cellular response, such as activation of calcium/calmodulin dependent kinase, and subsequently regulates the proliferation and differentiation of human epidermal keratinocytes.
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PMID:[Changes in the intracellular free calcium of cultured human epidermal keratinocytes]. 171 97

Interleukin 1 (IL1) increased phosphorylation of the small heat-shock protein (hsp 27) in MRC5 fibroblasts. The increase was maintained for at least 30 min, but levels had returned to pre-stimulation values by 2 h. When hsp 27 was metabolically labelled with [3H]leucine, about 15% was phosphorylated in resting confluent cells; this rose to 90% upon stimulation by IL1. Peptide maps of the three differently charged phosphorylated forms were consistent with their arising by phosphorylation of increasing numbers of serine residues. IL1 had the same effect on hsp 27 in pig articular chondrocytes, endothelial cells from human umbilical vein and an epidermoid carcinoma cell line (KB). Certain other agents were found selectively to increase phosphorylation of hsp 27 in MRC5 cells besides IL1 [and tumour necrosis factor (TNF)]. Platelet-derived growth factor had a similar effect to that of IL1; bradykinin, acid fibroblast growth factor and ATP caused an intermediate effect; phorbol myristate acetate (PMA) and 1-oleoyl-2-acetylglycerol had smaller effects. Dibutyryl cyclic AMP and forskolin had no effects on hsp 27 phosphorylation. When cells had been depleted of protein kinase C (PKC) by prolonged treatment with PMA, stimulation by IL1, TNF or bradykinin still increased hsp 27 phosphorylation. The stimulation by all three agents was also unaffected by the PKC inhibitor staurosporine. IL1, TNF and bradykinin each caused hsp 27 phosphorylation by a pathway independent of PKC. The results are consistent with IL1 activating a serine kinase which remains to be identified.
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PMID:Phosphorylation of the small heat-shock protein is regulated by interleukin 1, tumour necrosis factor, growth factors, bradykinin and ATP. 187 99

Previous studies using phorbol esters and cell-free preparations suggest that protein kinase C (PKC) may regulate Cl- secretion and apical membrane Cl- channels in airway epithelium. To determine whether PKC may be involved in receptor-mediated control of secretion, we measured the mass of diacylglycerol (DAG) generated by two Cl- secretagogues, isoproterenol and bradykinin. Bradykinin increased cellular DAG at concentrations similar to those that increase inositol phosphates, suggesting that bradykinin stimulates phosphatidylinositol hydrolysis, as observed in other systems. Isoproterenol also increased cellular DAG at concentrations similar to those that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. The beta-adrenergic receptor antagonist, nadolol, blocked and cell-permanent analogues of cAMP mimicked the effect of isoproterenol. However, isoproterenol does not stimulate phosphatidylinositol turnover. Simultaneous addition of maximal concentrations of isoproterenol and bradykinin produced additive increases in DAG. To test the possibility that the isoproterenol-induced increase in DAG came from phosphatidylcholine turnover, we measured the release of water-soluble choline metabolites and the incorporation of choline into cellular lipids. Although phorbol ester and bradykinin stimulated phosphatidylcholine turnover, isoproterenol did not. These results suggest that isoproterenol and bradykinin generate DAG from the following different lipid sources: bradykinin stimulates phosphatidylinositol hydrolysis to produce DAG; isoproterenol stimulates an increase in DAG from unknown sources. The data suggest that simultaneous activation of cAMP-dependent protein kinase and PKC may occur during receptor-mediated stimulation of Cl- secretion.
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PMID:Isoproterenol, cAMP, and bradykinin stimulate diacylglycerol production in airway epithelium. 216 9

Using 1-[4-(trimethylamino)phenyl]-6-phenyl-hexa-1,3,5-triene, a fluorescent probe that specifically labels the external leaflet of the plasma membrane of living cells, we examined the effects of antidiuretic hormone (ADH) and various agents known to raise intracellular adenosine 3',5'-cyclic monophosphate (cAMP) on the physical state of the plasma membrane of Madin-Darby canine kidney (MDCK) cells. In polarized cells grown as a monolayer, [desamino-Cys1, DArg8]-vasopressin (V2-agonist) elicited a biphasic decrease in the lipid order as estimated from the decrease in fluorescence anisotropy (from r = 0.317 to r = 0.304, 37 degrees C) of the apical domain of the plasma membrane, equivalent at the peak response (t = 5 min) to that produced by an upward shift in temperature of 5-6 degrees C. A similar response was obtained by adding dibutyryl cAMP to the monolayers. Experiments on cell suspensions further indicated that the biphasic decrease in lipid order could also be evoked by forskolin, prostaglandin E2, and bradykinin but not by bradykinin plus indomethacin and was inhibitable by the protein kinases inhibitor compound H7. These data demonstrate that the lipid order of the plasma membrane of MDCK cells can be modulated in situ by cAMP-dependent processes probably involving protein kinase A activity, i.e., that membrane "fluidity" might act in the regulation of the cellular function of living epithelial cells. They provide a rationale for the changes in lipophilic solute permeability that accompany the increase in water permeability of target cells on ADH administration.
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PMID:ADH modulates plasma membrane lipid order of living MDCK cells via a cAMP-dependent process. 216 61

In the neuroblastoma X glioma hybrid cell line NG108-15, bradykinin (BK) receptor stimulation induced a rapid and concentration-dependent rise in cytosolic free Ca2+ levels, as measured with the Ca2(+)-sensitive fluorescent dye fura-2. The Ca2+ transient was present in the absence of extracellular Ca2+ and was associated with a concentration-dependent production of inositol phosphates, particularly inositol trisphosphate (InsP3). Pretreatment of intact NG108-15 cells with forskolin or dibutyryl-cAMP plus isobutylmethylxanthine reduced BK-stimulated InsP3 production and the increase in cytosolic free Ca2+. Membranes prepared from forskolin- and [3H]inositol-pretreated NG108-15 cells also showed a diminished production of InsP3 elicited by guanosine 5'-[gamma-thio]triphosphate, NaF, or BK plus GTP. On the other hand, the Ca2+ sensitivity of membrane-associated phosphoinositide-specific phospholipase C (PI-PLC) was unaffected by forskolin pretreatment of intact NG108-15 cells. Collectively, these results suggest that A-kinase may inhibit receptor-mediated and postreceptor stimulation of PI-PLC in neuron-like cells, perhaps by impairing the coupling between a guanine nucleotide-binding protein and PI-PLC.
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PMID:Cyclic AMP inhibits inositol polyphosphate production and calcium mobilization in neuroblastoma X glioma NG108-15 cells. 216 7

In this study we investigated the role of protein kinases in activation of the Na(+)-H+ exchanger in inner medullary collecting duct (IMCD) cells. Monolayers, 24-48 h after achieving confluence, were made quiescent by 24 h incubation in 0.1% serum before study. Changes in pHi were measured with 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Phorbol myristate acetate (PMA), a synthetic analogue of diacylglycerol (DAG), was used to stimulate protein kinase C (PKC). In nominally HCO3(-)-free media containing 110 mM Na+ and 1 mM Ca2+, PMA addition increased pHi from 7.29 +/- 0.08 to 7.54 +/- 0.07 after 20 min. The increment in pHi was completely inhibited by 1 mM amiloride or by replacement of extracellular Na+ with choline but not inhibited by 1 mM N-ethylmaleimide, an inhibitor of active proton transport. Downregulation of PKC by overnight incubation of monolayers with PMA also prevented the rise in pHi upon subsequent challenge with PMA. Another active analogue of DAG, 1,2-dioleoyl-rac-glycerol, caused an increment in pHi similar to that produced by PMA, whereas 4 alpha-phorbol, an inactive analogue, did not stimulate Na(+)-H+ exchange. Bradykinin (10(-6) M), a phospholipase C-activating hormone, also induces alkalinization of IMCD cells similar to that produced by phorbol esters. Neither vasopressin (10(-7) M), which induces cellular accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) and activation of protein kinase A (PKA), nor 8-bromo-cAMP (1 mM) changed pHi. Therefore in the IMCD cell activation of PKC but not PKA stimulates a rise in pHi via the Na(+)-H+ exchanger.
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PMID:Na(+)-H+ exchange is stimulated by protein kinase C activation in inner medullary collecting duct cells. 217 60

Ligand stimulation of the platelet-derived growth factor receptor (PDGF-R) results in rapid activation of the receptor tyrosine kinase, stimulation of phosphoinositide hydrolysis, an increase in intracellular free Ca2+ concentration ([Ca2+]i), and, ultimately, cellular proliferation. In a previous study, we demonstrated that staurosporine, a known inhibitor of protein kinase C, blocked PDGF-induced [Ca2+]i increases in Swiss mouse 3T3 fibroblasts by a mechanism that appeared unrelated to inhibition of protein kinase activity (Olsen, R., Melder, D., Seewald, M., Abraham, R., and Powis, G. (1990) Biochem. Pharmacol. 39, 968-972). In the present study, we report that staurosporine inhibits ligand-dependent PDGF-R tyrosine kinase activation in cell-free receptor preparations and in intact Swiss 3T3 cells. At the same concentrations (10(-8)-10(-6) M), staurosporine suppressed both the tyrosine phosphorylation of phospholipase C activity and the hydrolysis of phosphoinositides induced by PDGF stimulation of intact cells. In contrast, guanine nucleotide-binding protein-dependent phospholipase C activation induced by bradykinin or fluoroaluminate anion was relatively insensitive to staurosporine. A preferential inhibitory effect of staurosporine on signal generation by the PDGF-R was indicated by findings that epidermal growth factor receptor (EGF-R) tyrosine kinase activity and EGF-dependent phospholipase C in A-431 carcinoma cells were approximately 100-fold less sensitive to this drug. These data indicate that submicromolar concentrations of staurosporine inhibit PDGF-dependent phosphoinositide hydrolysis and Ca2+ mobilization through a proximal inhibitory effect on ligand-induced activation of the PDGF-R tyrosine kinase.
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PMID:Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinase by staurosporine. 217 5

The direction of net fluid transport in the gut is determined by the algebraic sum of Na+ absorption and Cl- secretion. Na+ absorption by small intestinal villous cells and colonic surface cells is controlled primarily by electrically neutral (NaCl) and electrogenic (Na+-glucose, Na+-amino acid, amiloride-insensitive, and amiloride-sensitive Na+ conductance) entry processes in the apical membrane. Neutral NaCl entry appears to be the result of parallel Na+:H- and Cl-:HCO3- exchangers operating at equal stoichiometry. Uncoupled exchangers operating at different stoichiometry may result in net HCO3- absorption (jejunum), net HCO3- secretion (ileum and proximal colon) or HCO3-:Cl- exchange (distal colon). Increases in intracellular cyclic nucleotides and/or ionized Ca2+ inhibit NaCl entry and, in vivo, promote HCO3- and Cl- secretion. Cl- secretion by crypt cells is the result of cyclic nucleotide-mediated or Ca2+-mediated Cl- conductance channels in the apical membrane which allow Cl- to exit down an electrochemical gradient created by a basolateral NaKCl2 entry process. Cyclic nucleotides may act via specific A and G protein kinases. They also release Ca2+ from intracellular stores and thus could alter transport via Ca2+ (and calmodulin)-activated kinases. Ca2+-dependent secretory agents initiate phospholipid hydrolysis and stimulate secretion via the resulting hydrolytic products: arachidonic acid metabolites when bradykinin is the stimulus or diacylglycerol and/or inositol trisphosphate when acetylcholine is the stimulus. The arachidonic acid metabolites may then stimulate cyclic nucleotide production, while diacylglycerol activates a specific Ca2+/phospholipid-dependent protein kinase (C kinase), and inositol trisphosphate releases Ca2+ from the endoplasmic reticulum. The interrelationships between these intracellular messengers and their exact modes of action remain to be clarified.
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PMID:Regulation of water and ion movement in intestine. 240 30

The biochemical events encompassing the dephosphorylation of protein kinase C substrates by protein kinase A activators have been investigated in a neurotumor cell line, NCB-20. Treatment of [32P]orthophosphate-labeled cells with protein kinase A activators (e.g. forskolin, dibutyryl cAMP, prostaglandin E1) resulted in an inhibition of protein kinase C activity due to a failure of the protein kinase C complex to translocate into the membrane. Phospholipase C activity, as measured by the synchronous release of diacylglycerol and inositol phosphates (inositol 1,4,5-trisphosphate, inositol 1,4-bisphosphate, and inositol 1-phosphate) in response to bradykinin, was inhibited up to 50% following exposure to protein kinase A activators. At the same time, phospholipase C-specific inositol phospholipid substrates (phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate) were found to accumulate in NCB-20 cells following treatment with protein kinase A activators. This suggests that phospholipase C may be altered through protein kinase A-mediated protein phosphorylation. Second messenger generation (inositol phosphates, diacylglycerol, and Ca2+) is therefore inhibited through cyclic AMP-mediated shutdown of the inositol lipid cycle at the level of phospholipase C.
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PMID:Rapid dephosphorylation of protein kinase C substrates by protein kinase A activators results from inhibition of diacylglycerol release. 247 91

Muscarinic receptor stimulation increased the accumulation of 3H-inositol phosphates in PC12 cells whose phospholipids had been prelabeled with [3H]inositol. Muscarine also inhibited the increase in cyclic AMP (cAMP) accumulation caused by 5'-N-ethylcarboxamide adenosine or by vasoactive intestinal peptide. This effect of muscarine was apparently due to the inhibition of adenylate cyclase rather than to a stimulation of a cAMP specific phosphodiesterase. The muscarinic receptor antagonist pirenzepine inhibited both the stimulation of inositol-phospholipid metabolism and the inhibition of cAMP production with Ki values of 0.34 microM and 0.36 microM, respectively. PC12 cells contained a single class of N-[3H]methylscopolamine ([3H]NMS) binding sites. Competition studies with muscarine (KD, 15 microM) and pirenzepine (Ki, 0.12 microM) revealed no evidence for multiple muscarinic receptors. The Ki of pirenzepine for the inhibition of [3H]NMS binding and the inhibition of muscarinic actions is consistent with the possibility that this is not an M1 receptor. Muscarine inhibited cAMP accumulation in cells made deficient in protein kinase C; therefore, this protein kinase is probably not involved in mediating the inhibitory effect of muscarine. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate also inhibited cAMP accumulation in PC12 cells but the mechanism of this effect differed from that of muscarine. Bradykinin caused a large increase in the accumulation of 3H-inositol phosphates and [3H]diacylglycerol relative to muscarine but did not inhibit cAMP production. Oxotremorine inhibited cAMP accumulation but it did not stimulate inositol-phospholipid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic receptor stimulation increases inositol-phospholipid metabolism and inhibits cyclic AMP accumulation in PC12 cells. 254 58


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