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)

Octimibate inhibited ADP- and collagen-induced platelet aggregation in human, rabbit and rat platelet-rich plasma. Washed human platelets treated with octimibate had elevated cyclic AMP (cAMP) levels and cAMP-dependent protein kinase activity. When whole platelets were incubated with radiolabeled phosphate, octimibate produced an increase in the phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. This pattern of protein phosphorylation is identical to that observed when the platelets were treated with forskolin, phosphodiesterase inhibitors or other compounds that elevate platelet cAMP levels. Octimibate also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets, which is consistent with octimibate's ability to elevate platelet cAMP levels. When isolated platelet plasma membranes were treated with octimibate, adenylate cyclase activity was stimulated, reaching maximal activation at 1 microM octimibate. (The maximal activation of adenylate cyclase observed with octimibate is 70-75% of that observed with 10 microM PGE1.) This stimulation of platelet adenylate cyclase activity was enhanced by GTP. Octimibate competed for radiolabeled prostaglandin E1 and lloprost binding to isolated platelet membranes at submicromolar concentrations, but did not compete with radiolabeled prostaglandin D2 binding. These studies suggest that octimibate inhibits platelet aggregation by activating platelet adenylate cyclase through stimulation of platelet prostacyclin receptors.
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PMID:Octimibate inhibition of platelet aggregation: stimulation of adenylate cyclase through prostacyclin receptor activation. 217 92

Quantitative and qualitative changes in adrenoceptors under various conditions were studied by binding experiments. Chronic treatment with reserpine increased the level of alpha 2-adrenoceptors in rat vas deferens and hypoxia increased the level of alpha 1-adrenoceptors in rat cardiomyocytes. Adenosine receptor agonists increased the affinity of the alpha 2-adrenoceptor in rat vas deferens for the agonist with an increase in receptor-mediated responses. Thus two types of changes in receptor binding sites were observed. Next, changes in the GTP-binding (G) protein were studied. Activation of cyclic AMP-dependent protein kinase (PKA) decreased the ADP-ribosylation of Gi (41 K) protein by islet-activating protein (pertussis toxin, IAP). Purified Gi protein was phosphorylated by the enzyme. IAP-sensitive G protein-mediated coupling responses such as phosphatidylinositol turnover in differentiated HL-60 cells were also modified under this condition. These results indicated that phosphorylation of Gi by PKA caused a qualitative change of Gi. Lithium ions also decreased the ADP-ribosylation of Gi by IAP. Then it determined if the decrease was accompanied with a dissociation of the subunits of Gi. Phosphorylation of Gi by PKA impaired the dissociation of the subunits of Gi caused by Mg2+ and GTP gamma S, whereas lithium ions did not have any effect on their dissociation. Thus some conditions caused a functional change in the so-called "qualitative change" of Gi.
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PMID:The mechanism of changes in adrenoceptor-mediated responses. 217 4

Protein kinase C catalyzes phosphorylation of the rat skeletal muscle AMP-deaminase in the presence of calcium ions and phosphatidylserine. At the same time, the catalytic subunit of cAMP-dependent protein kinase fails to phosphorylate AMP-deaminase. Ca2+, phosphatidylserine-dependent phosphorylation decreases three-fold (from 0.6 to 0.2 mM) the Km value and does not affect Vmax. Protein kinase C-induced phosphorylation of AMP-deaminase, besides ADP-ribosylation, is suggested to be involved in regulating the AMP-deaminase activity in vivo.
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PMID:Phosphorylation of the skeletal muscle AMP-deaminase by protein kinase C. 229 22

alpha-Thrombin and phorbol 12,13-dibutyrate stimulated the mono(ADP-ribosyl)ation of a 42-kDa cytosolic protein of human platelets. This effect was mediated by protein kinase C activation and was inhibited by protein kinase C inhibitor staurosporine. It also was prevented by prostacyclin, which is known to inhibit the phospholipase C-induced formation of 1,2-diacylglycerol, which is one of the endogenous activators of protein kinase C. On sodium dodecyl sulfate/polyacrylamide gel electrophoresis, the 42-kDa protein that is ADP-ribosylated by alpha-thrombin was clearly distinct from the alpha subunits of membrane-bound inhibitory and stimulatory guanine nucleotide-binding regulatory proteins, respectively Gi alpha and Gs alpha; the 47-kDa protein that is phophorylated by protein kinase C in platelets; and the 39-kDa protein that has been shown to be endogenously ADP-ribosylated by agents that release nitric oxide. This information shows that agonist-induced activation of protein kinase leads to the ADP-ribosylation of a specific protein. This covalent modification might have a functional role in platelet activation.
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PMID:Agonist-induced ADP-ribosylation of a cytosolic protein in human platelets. 233 84

The validity of the hypothesis that cyclic AMP (cAMP) is the 2nd messenger for cell activation was reexamined. Some enzymological aspects of adenyl cyclase (AC) should cause concern: the lack of data on the stoichiometry of cAMP formation in mammalian systems and the unusual enzymatic properties, as well as lack of end-product inhibition and linearity. Furthermore, adenyl cyclase assays may lack precision and accuracy; this may depend on the organ studied. There are also problems of artefactual formation of cAMP during the work-up of cAMP extracts. Thus CrP, Pi, or ATP might influence this process and the actual measurement of cAMP, but solid data are apparently not available. Although a hormone-sensitive AC system has now been reconstituted from pure beta-adrenergic receptor, guanine nucleotide regulatory protein (Ns), and from bovine brain, the sensitivity to isoprenaline was very low and many questions remain--questions about the role of ions and Ns, in particular. The assumption that cAMP is the sole 2nd messenger is questioned since other nucleotides (AMP, ADP) and adenosine may change even more during hormone stimulation, and these compounds can also modulate protein kinase at concentrations often observed in vivo. Doubt over cAMP's role also stems from the observation that basal cAMP levels are sufficiently high to stimulate maximally protein kinase. Discrepancies between cAMP formation and lipolysis during isoprenaline or forskolin stimulation have been observed, and could indicate either compartmentalization of cAMP or alternatively disprove the cAMP hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is there a role for cAMP and adenyl cyclase? 241 Jul 32

The effects of sphingosine, the newly described inhibitor of the enzyme protein kinase C, on human platelet activation, were studied in order to gain further information on the role of protein kinase in platelet responses. Concentrations of the drug (5-20 microM) which had little effect on protein kinase C activation as measured by the phosphorylation of the 45 kDa and 20 kDa protein substrates induced by phorbol 12-myristate 13-acetate (PMA) and thrombin, strongly inhibited platelet aggregation induced by these agonists, as well as aggregation induced by ADP and ionomycin, which caused no detectable protein kinase C activation or 5-hydroxy[14C]tryptamine[( 14C]5HT) secretion. At approx. 10-fold higher concentrations (150-200 microM), sphingosine had significant inhibitory effects on PMA and thrombin-induced 45 kDa and 20 kDa protein phosphorylation. However, at these high concentrations, the drug caused extensive membrane damage/leakiness as suggested by the substantial release of [14C]5HT and [3H]adenine from pre-loaded platelets (50-70% release of both markers), and the total quenching of quin2 fluorescence by Mn2+ in the presence of the drug. Due to the increased membrane leakiness in the presence of the drug, an apparent potentiation of agonist-induced intracellular Ca2+ elevations in quin2-loaded platelets, as well as an increase in quin2 fluorescence with the drug alone (more than 50 microM) were also observed. Despite this, however, thrombin-induced [3H]arachidonate release was severely reduced in the presence of sphingosine, underlining the inhibitory effects at the membrane level. It is concluded that the weak, if any, inhibitory effects on protein kinase C at concentrations not affecting membrane integrity, as well as the inhibitory effects of sphingosine on platelet aggregation, make it an unsuitable compound as a tool for studies on platelet stimulus-response coupling.
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PMID:Weak inhibition of protein kinase C coupled with various non-specific effects make sphingosine an unsuitable tool in platelet signal transduction studies. 249 1

Extracellular ATP at 10 microM increased the concentration of cytoplasmic free Ca2+ ( [Ca2+]i) 3-fold in human neutrophils. The [Ca2+]i was measured by fura-2 fluorescence. The effect was rapid but transient: [Ca2+]i reached a maximum within 10 s and then returned to its resting value after 2-3 min. The rise in [Ca2+]i elicited by ATP was unaffected by the removal of extracellular Ca2+, indicating that the primary source of Ca2+ is from intracellular stores. In contrast to ATP, neither ADP nor AMP, at concentrations as high as 100 microM, caused any detectable changes in [Ca2+]i. Among other nucleotide triphosphates tested, UTP was as effective as ATP in causing a transient rise in [Ca2+]i, and prevented a subsequent response to ATP. Similarly, ATP prevented a subsequent response to UTP but the second response could be obtained when the initially added ATP was removed by the addition of hexokinase. Phorbol myristate acetate, the activator of Ca2+, phospholipid-dependent protein kinase, completely inhibited the ATP-induced increases in [Ca2+]i without affecting the basal [Ca2+]i level. The results suggest that extracellular ATP stimulates human neutrophils by causing the release of calcium from intracellular storage pools by mechanisms which can be inhibited by phorbol myristate acetate.
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PMID:ATP-induced calcium mobilization in human neutrophils. 249 55

Clonidine and morphine are known to produce tolerance and dependence in rat locus coeruleus (LC) neurons after chronic administration based on electrophysiological criteria. Previous studies have shown that morphine tolerance and dependence is associated with increases in levels of adenylate cyclase, pertussis toxin-mediated ADP-ribosylation of G-proteins, and cyclic AMP-dependent protein kinase in this brain region. The present study was aimed at investigating whether clonidine tolerance and dependence is also associated with alterations in these intracellular messengers. It was found that, similar to chronic morphine, chronic (2 weeks) clonidine administration, under conditions that produce electrophysiological evidence of tolerance and dependence in LC neurons, increased levels of adenylate cyclase activity and cyclic AMP-dependent protein kinase activity in this brain region, but not in several other regions studied, which included the frontal cortex, neostriatum, and dorsal raphe. However, the changes induced by chronic clonidine in the LC, at maximal doses and duration of treatment, were only approximately 50% in magnitude of those observed in response to morphine. Unlike chronic morphine, chronic clonidine produced no change in G-protein ADP-ribosylation levels in the LC. Chronic administration of a number of other drugs, namely diazepam, chloral hydrate, and dextromethorphan, which produce electrophysiological actions distinct from those of clonidine and morphine in the LC, failed to alter adenylate cyclase and cyclic AMP-dependent protein kinase in this brain region. The results indicate that increased levels of adenylate cyclase and cyclic AMP-dependent protein kinase represent common adaptations by LC neurons to chronic clonidine and morphine, and raise the possibility that such changes contribute to the development of clonidine and morphine tolerance and dependence in these neurons.
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PMID:Regulation by chronic clonidine of adenylate cyclase and cyclic AMP-dependent protein kinase in the rat locus coeruleus. 250 46

During ATP hydrolysis the K+-translocating Kdp-ATPase from Escherichia coli forms a phosphorylated intermediate as part of the catalytic cycle. The influence of effectors (K+, Na+, Mg2+, ATP, ADP) and inhibitors (vanadate, N-ethylmaleimide, bafilomycin A1) on the phosphointermediate level and on the ATPase activity was analyzed in purified wild-type enzyme (apparent Km = 10 microM) and a KdpA mutant ATPase exhibiting a lower affinity for K+ (Km = 6 mM). Based on these data we propose a minimum reaction scheme consisting of (i) a Mg2+-dependent protein kinase, (ii) a Mg2+-dependent and K+-stimulated phosphoprotein phosphatase, and (iii) a K+-independent basal phosphoprotein phosphatase. The findings of a K+-uncoupled basal activity, inhibition by high K+ concentrations, lower ATP saturation values for the phosphorylation than for the overall ATPase reaction, and presumed reversibility of the phosphoprotein formation by excess ADP indicated similarities in fundamental principles of the reaction cycle between the Kdp-ATPase and eukaryotic E1E2-ATPases. The phosphoprotein was tentatively characterized as an acylphosphate on the basis of its alkali-lability and its sensitivity to hydroxylamine. The KdpB polypeptide was identified as the phosphorylated subunit after electrophoretic separation at pH 2.4, 4 degrees C of cytoplasmic membranes or of purified ATPase labeled with [gamma-32P]ATP.
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PMID:Characterization of the phosphorylated intermediate of the K+-translocating Kdp-ATPase from Escherichia coli. 252 40

The activity of a purified cytosolic aminopeptidase (Mr 79,000) from monkey brain was stimulated about 4-fold by ATP-Mg2+. The stimulation was seen with either synthetic aminopeptidase substrates or natural peptides such as enkephalins. Both ATP and Mg2+ were required for stimulation, and ADP did not inhibit the stimulation. Non-hydrolysable analogues of ATP, deoxy-ATP and other nucleoside triphosphates stimulated to a lesser extent compared with ATP, whereas nucleoside mono- or di-phosphates were ineffective. The enzyme did not exhibit any ATPase activity. An ATPase inhibitor, orthovanadate, had no inhibitory effect on the ATP-Mg2+ stimulation. The aminopeptidase was not autophosphorylated by [gamma-32P]ATP and Mg2+, but in the presence of cyclic AMP-dependent protein kinase underwent phosphorylation on serine residue(s). Phosphorylation resulted in inactivation of the aminopeptidase activity, and also resulted in a decreased stimulation of the enzyme by ATP-Mg2+.
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PMID:Stimulation by ATP-Mg2+ and inactivation by cyclic-AMP-dependent phosphorylation of a cytosolic monkey brain aminopeptidase. 252 25


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