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)

Mastoparan, a tetradecapeptide purified from wasp venom, stimulates insulin and glucagon release by rat pancreatic islets in a dose-related manner. In perifusion experiments, mastoparan produces monophasic hormone release, which ceases within 10 min of removal of the peptide. After exposure of the isles to mastoparan, glucose-induced insulin release is clearly retained. In incubation experiments, mastoparan-induced insulin release is greatly blocked by pretreatment of the islets with pertussis toxin or neomycin (inhibitor of phosphoinositide turnover) or by lowering the ambient temperature to 17 C. Pretreatment of the islets with nifedipine (calcium channel blocker), H-7 (inhibitor of A- and C-kinase), somatostatin, or divalent cation-free medium does not affect the response to mastoparan. Pretreatment with parabromophenacylbromide (phospholipase-A2 inhibitor) does not block the response induced by a high concentration of (58 microM) mastoparan. The peptide does not stimulate insulin synthesis during 30 min of incubation. Mastoparan raises the cytosolic free Ca2+ concentration, measured by fura-2, in isolated islet cells at normal (1.9 mM) and very low (6.5 microM) extracellular Ca2+ concentrations. Intravenous administration of mastoparan in rats causes a significant elevation of both insulin and glucagon. Together with the previous data, we conclude that mastoparan stimulates islet hormone release through a temperature-dependent process mediated by pertussis toxin-sensitive GTP-binding protein(s). Activation of phospholipase-C and liberation of intracellular Ca2+ are likely to be coupled to exocytosis. Ca2+ influx through the Ca2+ channel and protein kinase-A and -C appear not to be involved in mastoparan's hormone-releasing action. Phospholipase-A2 may be involved in the hormone release induced by low, but not high, concentrations of the peptide.
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PMID:Mastoparan-induced hormone release from rat pancreatic islets. 172 98

Three G proteins from human brain membranes were purified to near homogeneity by conventional techniques including preparative electrophoresis. These G proteins were characterized by their ability to bind GTP, GDP and GTP analogs. Two of these proteins have molecular weights of 50,000 (G50) and 36,000 (G36), as determined on SDS-gels. G36 was ADP-ribosylated by pertussis toxin. Thus, G50 could represent a Gs alpha subunit, whereas G36 could be Gi alpha or Go alpha. G50 was phosphorylated by cAMP dependent protein kinase and protein kinase C. G36 was phosphorylated by a protein kinase independent of calcium and phospholipid, a proteolytic product of protein kinase C, analogous to protein kinase M. Phosphorylation of G36 by this protein kinase induced a dramatic decrease in its GTPase activity. The third G protein, of molecular weight 22,000 probably belongs to the group of monomeric G proteins possessing functional similarities with ras gene products. The regulation of G proteins involving calcium-dependent and independent pathways is delineated.
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PMID:Purification and characterization of G proteins from human brain: modification of GTPase activity upon phosphorylation. 178 75

Cyclic GMP mediates vascular smooth muscle relaxation to a variety of drugs and naturally-occurring substances. The reduction of intracellular Ca2+ levels is believed to underlie this action, but the mechanism of this effect is unknown. In order to test the hypothesis that inhibition of guanine nucleotide-binding protein function is involved in the actions of cGMP, the effects of cGMP-dependent protein kinase on the phosphorylation of both pertussis toxin-sensitive (Gi/Go) and insensitive (Gz) G-proteins were examined in vitro. None of these proteins were effective substrates for either cGMP- or cAMP-dependent protein kinases, despite the fact that assay conditions were designed to detect poorly phosphorylated substrate proteins. In line with these observations, atriopeptin II did not inhibit angiotensin II-treated inositol phosphate formation in cultured vascular smooth muscle cells. These results suggest that phosphorylation by cGMP-dependent protein kinase of these G-proteins is not the major mechanism by which cGMP reduces intracellular Ca2+ levels in vascular smooth muscle.
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PMID:Pertussis toxin-sensitive and insensitive guanine nucleotide binding proteins (G-proteins) are not phosphorylated by cyclic GMP-dependent protein kinase. 183 99

MEPP frequency (f) was measured in mouse phrenic nerve hemidiaphragm preparations during exposure to adrenoceptor agonist and antagonist drugs. Epinephrine, norepinephrine (NE), and phenylephrine caused a concentration-dependent increase in frequency that was blocked by prazosin but not by yohimbine or nadolol. Isoproterenol had no effect on MEPP(f). The response to NE was not affected by prior incubation of the tissues with pertussis toxin. The response was, however, reduced or abolished by prior exposure to drugs, the actions of which include protein kinase inhibition, and also to a calmodulin inhibitory concentration of W-7. H-7, an inhibitor of protein kinase C and of cyclic nucleotide-dependent kinases, was ineffective. The response to NE was enhanced by 10 mM Li+. The data indicate the existence of a presynaptic alpha 1-adrenoceptor in the motor neuron terminal and suggest that modulation of transmitter release might be mediated by inositol triphosphate liberation, Ca2+ release into the cytosol and activation of a calmodulin-dependent system.
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PMID:Transduction of the modulatory effect of catecholamines at the mammalian motor neuron terminal. 184 23

We examined the possibility that, in addition to stimulation of guanylate cyclase (GC), atrial natriuretic peptide (ANP) also activates phospholipase C (PLC) in cultured rat inner medullary collecting tubule (RIMCT) cells. ANP (10(-12)M) causes marked release of inositol trisphosphate (IP3) at a concentration that does not stimulate GC. Concentrations of ANP that stimulate GC (greater than or equal to 10(-10) M) result in attenuated IP3 release. Similarly, exogenous dibutyryl guanosine 3',5'-cyclic monophosphate (10(-6) M) markedly inhibits the response to 10(-10) M ANP. Inhibition of cyclic nucleotide-dependent protein kinase by H 8, but not inhibition of protein kinase C by H 7, restores the response to 10(-8) and 10(-6) M ANP. Therefore, activation of cyclic nucleotide-dependent protein kinase inhibits ANP-stimulated PLC activity. Activation of protein kinase C by phorbol 12-myristate-13-acetate (PMA) decreases ANP-stimulated IP3 production. Pretreatment with H 7, but not H 8, prevents inhibition by PMA. To explore a potential role for G proteins, we examined the effect of guanine nucleotide analogues on ANP-stimulated IP3 production in saponin-permeabilized cells. ANP-stimulated IP3 production is enhanced by GTP gamma S and is inhibited by GDP beta S. Similarly, preincubation with pertussis toxin prevents ANP-stimulated IP3 release. We conclude that ANP stimulates PLC in RIMCT cells via a pertussis toxin-sensitive G protein. Stimulation of PLC is inhibited on activation of either cyclic nucleotide or Ca2+-phospholipid dependent protein kinases.
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PMID:ANP stimulates phospholipase C in cultured RIMCT cells: roles of protein kinases and G protein. 184 66

Pretreatment of partially purified inhibitory GTP-binding protein (Gi, 41 kDa) with activated cyclic AMP-dependent protein kinase (PKA) decreases its ADP-ribosylation by islet-activating protein (pertussis toxin, IAP). We examined whether this decrease was associated with dissociation of the trimer of alpha beta gamma-subunits of Gi protein into alpha-subunits and beta gamma-subunits. Results showed that phosphorylation of the Gi protein by PKA impaired its dissociation into alpha-subunits and beta gamma-subunits by 50 mM Mg2+ and 100 microM GTP gamma S. The results suggested that phosphorylation of the Gi protein by PKA possibly caused a conformational change of the trimer Gi protein.
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PMID:Phosphorylation of Gi protein by cyclic AMP-dependent protein kinase inhibits its dissociation into alpha-subunits and beta gamma-subunits by Mg2+ and GTP gamma S. 190 64

Recombinant monocyte-chemotactic and activating factor (rMCAF; alternative acronyms MCP-1, TDCF, human JE) induced migration of human monocytes across polycarbonate or nitrocellulose filters. Maximal induction of migration was observed at a concentration of 10 ng/ml (10(-9) M). Checkerboard analysis revealed that rMCAF elicited true gradient-dependent chemotactic migration, although a gradient independent chemokinetic effect was observed at low concentrations (1-5 ng/ml). rMCAF caused a rapid (less than 5 s) and transient (approximately 1.5 min) increase of free cytosolic Ca2+ ions, as assessed by the fura-2 probe. No Ca2+ increase was detected in neutrophils or lymphocytes stimulated by rMCAF. Studies conducted in the absence of extracellular Ca2+ or in the presence of Ni2+ (an inhibitor of Ca2+ influx) suggested that the increase of intracellular Ca2+ induced by rMCAF is dependent on the influx of extracellular Ca2+ through plasma membrane channels. Bordetella pertussis toxin inhibited the intracellular Ca2+ elevation and chemotaxis caused by rMCAF. The possible involvement of Ca(2+)-dependent protein kinases in rMCAF signaling pathway(s) was explored using inhibitors. Inhibitors of GMP-dependent kinase and myosin L chain kinase had no effect on rMCAF-induced monocyte migration. In contrast, protein kinase C/cAMP-dependent kinase inhibitors (such as, C-I, H-7, HA-1004, KT5720, and Staurosporine) markedly decreased rMCAF induced chemotaxis suggesting the involvement of a serine/threonine protein kinase, possibly protein kinase C, in rMCAF signaling pathway.
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PMID:The signal transduction pathway involved in the migration induced by a monocyte chemotactic cytokine. 191 57

Preincubation of Fura 2-loaded rat myometrial cells with H-8, an inhibitor of protein kinase A, for 1 h reversed the inhibitory effects of 8-(4-chlorophenylthio)-cAMP (CPTcAMP) on the oxytocin-stimulated increase in (Ca2+)i (intracellular free calcium), with an EC50 of 47 microM. H-8 also prevented the inhibition by relaxin and isoproterenol of the oxytocin-induced increase in (Ca2+)i. The EC50 of H-8 in reversing the relaxin effect was 42 microM. H-8 reversal of the effect of relaxin on (Ca2+)i was evident both in the absence of extracellular calcium and in cells pretreated with pertussis toxin. H-8 also reversed the inhibitory effects of relaxin and CPTcAMP on the oxytocin-induced increase in [3H]inositol phosphate formation and [3H]phosphoinositide hydrolysis. Preincubation of myometrial cells for 1 h with H-7, another protein kinase inhibitor, only partially attenuated the inhibition by relaxin and CPTcAMP of the oxytocin-induced increase in (Ca2+)i and [3H]inositol phosphate formation at concentrations 4-5 times greater than those of H-8. Acute (15-min) exposure to phorbol myristate acetate (1.0 microM) did not affect basal (Ca2+)i or the oxytocin-stimulated increases in (Ca2+)i or inositol phosphate formation. These results imply a regulatory role for protein kinase A in the inhibition of the oxytocin-induced increase in (Ca2+)i and inositol phosphate formation by relaxants.
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PMID:Involvement of protein kinase A in the regulation of intracellular free calcium and phosphoinositide turnover in rat myometrium. 196 19

We studied the effects of ATP-gamma-S on the T, N and L calcium current components of nodose ganglion neurons using the whole cell variation of the patch clamp technique. ATP-gamma-S can serve as a phosphate donor in kinase-mediated reactions, the donated phosphate group being resistant to the action of phosphatases. We therefore compared the effect of ATP-gamma-S to that of the catalytic subunit of the cyclic AMP-dependent protein kinase (AK-C), included in the recording pipette with 5 mM ATP. AK-C (50 micrograms/ml) had no effect on the T current, and caused a approximately 30% increase in currents containing the N and L components during a 20-min recording, as compared to a approximately 45% decrease in control currents. In contrast, in the presence of 2.5 mM ATP-gamma-S, T currents declined approximately 30%, and currents containing the N and L components declined to a greater extent than control currents, about 65%. In addition, the time to peak current was increased from approximately 14 ms to approximately 40 ms. This effect of ATP-gamma-S on calcium currents was similar to that of certain neurotransmitters or GTP-gamma-S, an activator of G proteins, except that the effects of ATP-gamma-S were delayed 5-7 min relative to GTP-gamma-S. The effects of both ATP-gamma-S and GTP-gamma-S were reduced or abolished in neurons treated with pertussis toxin. We conclude that AK-C regulates neuronal calcium currents, presumably by phosphorylation of channels or associated proteins, and that the ATP-gamma-S-induced reduction of calcium currents cannot be due to its serving as a phosphate donor for endogenous AK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The reduction of neuronal calcium currents by ATP-gamma-S is mediated by a G protein and occurs independently of cyclic AMP-dependent protein kinase. 196 68

The kappa-selective opioid peptide dynorphin A (DYN) inhibits neuronal adenylate cyclase activity and reduces neuronal voltage-dependent calcium currents. It is not yet known, however, whether the regulation of calcium channel activity is dependent on or independent of the adenylate cyclase/cAMP system. We used the whole-cell variation of the patch clamp technique to show that DYN reversibly reduced, in a naloxone-sensitive manner, calcium currents in acutely dissociated rat nodose ganglion neurons. DYN slowed the rate of current activation and had a greater effect on currents evoked from relatively negative holding potentials. These actions were mimicked by guanosine 5'-[gamma-thio]triphosphate, which activates GTP-binding proteins (G proteins), and were blocked by pretreatment with pertussis toxin, which inactivates Gi- and Go-type G proteins. In contrast, calcium currents recorded in the presence of the catalytic subunit of the cAMP-dependent protein kinase (AK-C), included in the recording pipette, increased in magnitude throughout the recording. DYN was applied to neurons before and after the effect of AK-C became apparent; the reduction of calcium currents by DYN was greater in the presence of AK-C than in its absence. We conclude that the acute reduction of neuronal calcium currents by DYN occurred by means of activation of pertussis toxin-sensitive Gi- or Go-type G proteins. The persistence of the action of DYN in the presence of AK-C indicates, however, that this effect was independent of a reduction of the activity of the adenylate cyclase/cAMP system and suggests in addition that phosphorylated channels may be preferentially inhibited by DYN.
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PMID:Dynorphin A and cAMP-dependent protein kinase independently regulate neuronal calcium currents. 197 50


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