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)

An intracellular pool of Na channel alpha subunits has been detected in developing brain cells in vivo and in vitro by phosphorylation with cAMP-dependent protein kinase, immunoprecipitation with specific antiserum, and NaDodSO4 gel electrophoresis or by radioimmunoassay. These alpha subunits are membrane-bound, contain complex carbohydrate chains, and have an apparent molecular weight of 260,000 like mature alpha subunits. In contrast to mature alpha subunits, the intracellular subunits are not covalently attached to a beta 2 subunit, and they do not bind saxitoxin with high affinity. They comprise 67-77% of the total immunoreactive alpha subunit in developing rat brain cells but are not a prominent component in the adult brain. It is proposed that this intracellular pool of alpha subunits forms a ready reserve of preformed subunits for incorporation into the surface membrane during periods of active membrane biogenesis. The results suggest that disulfide linkage of the alpha and beta 2 subunits, insertion into the cell surface membrane, and attainment of a functional conformation are closely related late events in the biogenesis of the Na channel. These processes may regulate the number of functional Na channels in the developing brain.
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PMID:A large intracellular pool of inactive Na channel alpha subunits in developing rat brain. 241 Sep 8

The phosphorylation and dephosphorylation of the dihydropyridine-sensitive Ca2+ channel was studied in transverse-tubule membranes isolated from rabbit skeletal muscle. Exposure of these membranes to either the cAMP-dependent protein kinase or a Ca2+/calmodulin-dependent protein kinase resulted in a rapid phosphorylation of a protein with properties similar to the major component of the skeletal muscle Ca2+ channel. The molecular mass of the phosphoprotein was 140 or 160 kDa, depending on the electrophoretic conditions. The stoichiometry of the phosphorylation was calculated to be 0.4-1.0 mol of phosphate per mol of protein. Neither the rate nor the extent of phosphorylation was affected by dihydropyridines. Limited proteolytic digestion of the protein that had been phosphorylated by either or both protein kinases yielded a single phosphopeptide of approximately equal to 5.4 kDa. The Ca2+-dependent phosphatase calcineurin dephosphorylated the membrane-bound Ca2+ channel that had been previously phosphorylated by either protein kinase. The results suggest that the major component of the dihydropyridine-sensitive Ca2+ channel from skeletal muscle can be effectively phosphorylated and dephosphorylated in its native state by cAMP- and Ca2+-dependent processes.
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PMID:Phosphorylation and dephosphorylation of dihydropyridine-sensitive voltage-dependent Ca2+ channel in skeletal muscle membranes by cAMP- and Ca2+-dependent processes. 242 10

Our previous work demonstrated that 8-bromo-cAMP promotes the secretion of both hCG and progesterone by cultured cytotrophoblasts. This study was conducted to characterize the adenylate cyclase of cytotrophoblasts and to examine the effects of agents that stimulate adenylate cyclase on hCG secretion. Adenylate cyclase activity was detected in purified cytotrophoblasts, as were membrane-bound stimulatory and inhibitory guanine nucleotide regulatory proteins, Gs and Gi. Adenylate cyclase was stimulated by MnCl2 and MgCl2, and the effects of MgCl2 were amplified by the GTP analog guanylylimidodiphosphate. Cholera toxin stimulated both cAMP and hCG production by cultured cytotrophoblasts, confirming the coupling of Gs to the adenylate cyclase. Forskolin also stimulated adenylate cyclase, cAMP synthesis, and hCG secretion. Pertussis toxin did not affect hCG secretion in either the absence or presence of forskolin. 8-Bromo-cAMP stimulated cytotrophoblast protein kinase activity, resulting in the increased phosphorylation of a protein with a mol wt of about 70,000, and produced a marked stimulation of hCG secretion. Our findings suggest that the level of expression of adenylate cyclase activity is one determinant of the endocrine function of the differentiating trophoblast.
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PMID:Adenylate cyclase in human cytotrophoblasts: characterization and its role in modulating human chorionic gonadotropin secretion. 244 28

Interferons, via specific membrane-bound receptors, induce various cellular functions of which antiviral protection is the most extensively studied. We have previously reported the existence of interferon antagonists (referred to as sarcolectins) in various tissue extracts from placental blood, cartilage, brain, muscle, or from sarcomas. These sarcolectins have been fully characterized and purified to homogeneity. In interferon-treated cells, they restore virus sensitivity 4-6 h after the establishment of antiviral protection. In the present study we investigate the effect of sarcolectins on the steady state levels of two double-stranded RNA dependent enzymes, 2-5A (p chi (A2'p)nA) synthetase and protein kinase. Several authors have previously emphasized the role of these enzymes in the mechanism of interferon's antiviral action. Interferon promotes a 4-8 fold increase in protein kinase and 2-5A synthetase in cells. Addition of sarcolectin 5 h after interferon results in a dramatic reduction in the steady state levels of both these enzymes, as shown by their decreased activity and yield observed in Western blot assays. The degradation of the antiviral response in sarcolectin-treated cells might therefore be at least partially attributed to a reduced synthesis of protein kinase and 2-5A synthetase. Since there are no direct interactions between sarcolectins and interferon or its receptors, it can be postulated that sarcolectins exert their effect through these interferon-dependent proteins. We postulate that the opposing biological effects of interferon and sarcolectins strike a balance which may, however, be modified in one direction or the other, depending on their respective concentrations.
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PMID:Interferon- and sarcolectin-dependent cellular regulatory interactions. 246 34

The intracellular signal transduction mechanism leading to desmosome formation in low-calcium-grown keratinocytes after addition of calcium to the medium was studied by immunofluorescence using antibodies to desmoplakins I and II (cytoplasmic desmosomal proteins) and by electron microscopy before and after addition of calcium; protein kinase C (PKC) activators 12-O-tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-dibutyrate (PDBu), and 1,2-dioctanoylglycerol (DOG); calcium ionophore A23187; selective PKC inhibitors 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and staurosporine; and a Ca2+/calmodulin-dependent kinase inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). In previous studies using a low-calcium-grown human epidermal squamous cell carcinoma, we have shown that an increase in extracellular Ca2+ caused a four-fold increase in PKC activity and addition of TPA (10 ng/ml) induced a transient increase in membrane-bound PKC activity in association with cell-cell contact formation. The present study showed that TPA (10 ng/ml). PDBu (10 ng/ml), and DOG (1 mg/ml) induced a rapid cell-cell contact and redistribution of desmoplakins from cytoplasm to the plasma membrane with desmosome formation within 60-120 min, which was similar, although less marked, to the effect of increased Ca2+. The TPA-induced desmosome formation was inhibited by selective PKC inhibitors, H-7 (20 microM) or staurosporine (100 nM). On the other hand, calcium ionophore A23187 induced only a temporary increase in the number of desmoplakin-containing fluorescent spots in the cytoplasm and a temporary cell-cell attachment without desmosome formation. The calcium-induced desmosome formation was partially inhibited by 20-100 microM H-7 or 100 nM staurosporine; however, it was not inhibited by W-7 at a concentration of 25 microM, at which this agent selectively inhibits calmodulin-dependent protein kinase. These results suggest that PKC activation plays an important role in desmoplakin translocation from the cytoplasm to the plasma membrane as one of the processes of calcium-induced desmosome formation.
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PMID:Involvement of protein kinase C in translocation of desmoplakins from cytosol to plasma membrane during desmosome formation in human squamous cell carcinoma cells grown in low to normal calcium concentration. 250 26

PTH binds to specific receptors that are coupled to adenylate cyclase and activate cAMP-dependent protein kinase. Since it has been shown that PTH activates phospholipid inositol metabolism, we investigated whether PTH influences protein kinase-C (PKC) activity in rat osteosarcoma (ROS) cells 17/2.8 that contain a large number of PTH receptor. Incubation of ROS cells with PTH or phorbol 12-myristate 13-acetate (PMA) for 1-30 min caused a rapid and transient decrease in PKC activity in the cytosol, which was associated with a transient increase in PKC activity in the membrane fraction. After 1, 5, 15, and 30 min of incubation with PTH, cytosolic PKC activity decreased to 57%, 74%, 84%, and 93% of the control value, whereas membrane PKC activity increased to 156%, 122%, 111%, and 106% of the control value, respectively. After PMA treatment for 1, 5, 15, and 30 min, cytosolic PKC activity decreased by 81%, 74%, 63%, and 44%, whereas membrane-bound PKC activity increased by 83%, 44%, 28%, and 17%, respectively. The effects of PTH and PMA on PKC were dose dependent, with ED50 values of 0.3 nM PTH and 4 nM PMA. Chronic treatment of ROS cells for 3 days with PMA caused depletion of total PKC activity in cytosolic and membrane fractions to less than 10% of that in control cells. Conversely, chronic treatment of ROS cells with PTH did not deplete PKC. In addition, chronic treatment of ROS cells with PTH inhibited the responsiveness of PKC activity to subsequent acute PTH challenge, but not to acute PMA challenge, suggesting specific desensitization of this response by PTH. Activation of cytosolic PKC by diolein, phosphatidylserine, and calcium caused phosphorylation of many cytosolic proteins, including those having apparent mol wt of 39K, 35K, 33K, 25K, 19K, and 16K. Pretreatment of ROS cells with PTH resulted in a transient decrease in the phosphorylation of these cytosolic proteins by PKC. This decrease in cytosolic protein phosphorylation by treatment with PTH is temporally associated with PTH-stimulated translocation of PKC activity from the cytosol to the membranes. These data suggest a potential role for PKC in the mechanism of action of PTH in ROS cells.
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PMID:Parathyroid hormone causes translocation of protein kinase-C from cytosol to membranes in rat osteosarcoma cells. 253 72

Loss of membrane-bound beta-receptors in the myocardium of spontaneously hypertensive rats has been explained on the basis of enhanced agonist-induced desensitization. However, in both cardiac myocytes and cell-free preparations, isoproterenol and cyclic AMP-dependent protein kinase are less effective in desensitizing beta-receptors from hypertensive compared to normotensive animals. Reconstitution of cardiac membrances from hypertensive rats with cytosol from normotensive controls restores the ability of isoproterenol and protein kinase A to desensitize beta-receptors. Impaired desensitization in spontaneously hypertensive rats is, therefore, not due to intrinsic defects of the beta-receptor but, rather, to absence of regulatory cytosolic factor(s).
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PMID:Cytosolic factor(s) determines the impaired desensitization of beta-adrenoceptors in the myocardium of spontaneously hypertensive rats. 253 33

Polymorphonuclear leukocytes (PMNL) release superoxide anions formed by a membrane-bound NADPH oxidase induced by stimulations. Properties of the inducers and their antagonists indicate that Ca2+, GTP-binding protein (G-protein), phospholipase C and Ca2+, phospholipid-dependent protein kinase (C-kinase) are mainly associated with the stimulation of receptors. Low concentrations of ATP induce the oxidase accompanied by the increase in the intracellular Ca2+ due to the flux from the medium and the storage site. ATP-gamma-S, UTP and ITP are effective but mononucleotides, dinucleotides, GTP and CTP are not. Leukotriene B4 (LTB4) which acts as a chemotactic agent and the inducer of the NADPH oxidase is catabolized. It is hydroxylated by a specific cytochrome P450 and then oxidized to a carboxy derivative by a cytosolic alcohol dehydrogenase and a microsomal aldehyde dehydrogenase in PMNL. Active NADPH oxidase was obtained by incubating membrane and cytosolic components of resting PMNL in the presence of sodium dodecyl sulfate (SDS). Two cytosolic components were obtained by an affinity chromatography on 2',5'-ADP Sepharose. One component is active in the presence of GTP or GTP-gamma-S and the other component in the presence of another cytosolic fraction.
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PMID:Metabolism of stimulated polymorphonuclear leukocytes. 254 77

The molecular basis of opioid receptor mechanisms was studied in reconstitution experiments using purified or membrane-bound opioid receptors and purified GTP-binding proteins (G-proteins). mu-Opioid receptor exclusively purified from rat brains was reconstituted with G-proteins in lipid vesicles. The mu-agonist stimulated the G-protein activity in both G1 or Go-reconstituted vesicles. The stoichiometry revealed that one molecule of mu-receptor is functionally coupled to plural numbers of Gi or Go molecules and that mu-receptor exists in at least two different subtypes, mu i and mu o, separately coupled to Gi and Go, respectively. In addition, when the mu-receptor was phosphorylated by cAMP-dependent protein kinase, the mu-agonist-stimulation of G-protein activity disappeared, while the guanine nucleotide-sensitivity of agonist binding was unchanged. These findings suggest that there are independent domains in the receptor which are related to functional coupling to G-protein and to the agonist-binding modulation by G-protein. kappa-Opioid receptor agonist inhibited the G-protein activity in guinea pig cerebellar membranes. Further experiments revealed that the kappa-opioid receptor is functionally coupled to an inhibition of phospholipase C activity via an inhibition of Gi-activity. Such a receptor-mediated inhibition of G-protein activity may be the first demonstration of a signal transduction mechanism. The delta-opioid receptor agonist showed no effect on G-protein activity in guinea pig striatal and rat cortical membranes, while it stimulated it in NG108-15 cells. In all these membranes, the delta-agonist binding was markedly reduced by GTP gamma S in the presence of MgCl2. These findings suggest that delta-receptors in the brain might be coupled to G-protein without signal transduction.
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PMID:[Molecular pharmacology of opioid receptor mechanisms]. 255 62

Three systems mediate the fluxes of calcium across heart sarcolemma: the slow calcium channel (influx), the ATP-dependent calcium pump (efflux), and the Na+/Ca2+ exchanger (efflux, but possibly also influx). Calmodulin regulates the pumping ATPase by direct interaction and also by activating a protein kinase. The Na+/Ca2+ exchanger is modulated by calmodulin via a phosphorylation-dephosphorylation cycle. Both the kinase and the phosphatase are membrane-bound and calmodulin-sensitive. The kinase has higher Ca2+ affinity than the phosphatase.
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PMID:Calmodulin in the regulation of calcium fluxes in cardiac sarcolemma. 257 85


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