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)

The role of the A2A adenosine receptor in regulating voltage-sensitive calcium channels (VSCCs) was investigated in PC12 cells. Ca2+ influx induced by membrane depolarization with 70 mM K+ could be inhibited with CGS21680, an A2A receptor-specific agonist. Both L- and N-type VSCCs were inhibited by CGS21680 treatment. Effects of adenosine receptor agonists and antagonists indicate that the typical A2A receptor mediates inhibition of VSCCs. Cholera toxin (CTX) treatment for 24 h completely eliminated the CGS21680 potency. Similar inhibitory effects on VSCCs were obtained by membrane-permeable activators of protein kinase A (PKA). These effects were blocked by Rp-adenosine-3',5'-cyclic monophosphothioate, a PKA inhibitor. The data suggest that activation of the A2A receptor leads to inhibition of VSCCs via a CTX-sensitive G protein and PKA. ATP pretreatment caused a reduction in subsequent rise in cytosolic free Ca2+ concentration induced by 70 mM K+, presumably by inactivation of VSCCs. Simultaneous treatment with ATP and CGS21680 produced significantly greater inhibition of VSCCs than treatment with CGS21680 or ATP alone. Furthermore, the CGS21680-induced inhibition of VSCCs was not affected by the presence of reactive blue 2. CGS21680 still significantly inhibited ATP-evoked Ca2+ influx without VSCC activity after cobalt or 70 mM K+ pretreatment. These data suggest that the A2A receptor-sensitive VSCCs differ from those activated by ATP treatment. Although A2A receptors induce inhibition of VSCCs as well as ATP-induced Ca2+ influx, the two inhibitory effects are clearly distinct from each other.
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PMID:Inhibition of voltage-sensitive calcium channels by the A2A adenosine receptor in PC12 cells. 972 51

Cyclic AMP-Phosphodiesterases (cAMP-PDEs) catalyse the hydrolysis cAMP to AMP and thus serve to modulate the ligand-->adenylate cyclase-->cAMP-->PKA signal transduction pathway. PDEs exist as a multigene family of enzymes that bear significant sequence homology in the catalytic domains. The sequence alignment of these domains has revealed the presence of two histidine motifs: motif I, HNXXH, and motif II, HDXXH. These amino acid sequences are canonical motifs, which act as ligands for divalent metal cations required for catalytic activity. In this paper, we report human monocyte PDE4A to be a zinc-binding protein. Substitution by site-directed mutagenesis of either histidine in motif I by serine, which is not a ligand for metals, results in complete loss of catalytic activity and loss of sensitivity to divalent metal cation activation. However, similar mutations in motif II gave proteins that retained both approximately 50% of initial activity and the ability to respond differentially to Mg2+, Mn2+ and Co2+. Moreover the motif II mutants exhibited both functional group requirements and retained their pKa values. When the inactive mutants were affinity-labelled with 8-BDB-TcAMP and probed with antibody against cAMP or antibody against PDE4A, Western blots were unaltered. These results show that the conserved histidines in motif I are an absolute requirement for catalytic activity, whereas motif II histidines are required only to achieve maximum activity.
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PMID:Critical role of conserved histidine pairs HNXXH and HDXXH in recombinant human phosphodiesterase 4A. 975 17

Heavy metal ions can be released by corroding metallic implants into the surrounding tissue. When they enter blood vessels some of them are carried by proteins like albumin and can be taken up by endothelial cells lining the vessels. To study their involvement in the inflammatory response we investigated heavy metal ion induced effects in cultured human vascular endothelial cells (HUVECs). NiCl2 and CoCl2 upregulate, especially in concentrations of 1 mM, the expression of adhesion molecules (e.g., E-selectin and intercellular adhesion molecule-1), as well as the cytokines IL-6 and IL-8, as shown by enzyme immunoassay and Northern blot analysis. In addition, possible signal transduction mechanisms were elucidated. The HUVECs were treated with various selective inhibitory drugs followed by the incubation of metal ions before measuring the expression of the above-mentioned endothelial factors. Two protein kinase inhibitors (H-7 and H-8) strongly repressed Ni2+ and Co2+ enhanced expression, as did the phospholipase A2 inhibitor quinacrine. Other selective inhibitors of protein kinases C or A, or cGMP-dependent protein kinases, as well as calcium antagonists like 1,2-bis(2-aminophenoxy)ethan-N,N,N',N'-tetraacetic acid and 3,4,5-trimethoxybenzosaure 8-(diethylamino)-octylester and inhibitors of receptor mediated endocytosis (primary amines), had no influence. We showed that NiCl2 and CoCl2 activate the translocation of the transcription factor nuclear factor (NF)-kappaB into the cell nucleus and enhance its binding to a NF-kappaB consensus sequence as shown by mobility shift analysis. Furthermore, we demonstrated the activation of AP-1. Despite the repression of heavy metal induced adhesion molecule synthesis, we did not detect any inhibition of NF-kappaB translocation by H-7 or H-8. Therefore, it must be concluded that heavy metal ions like Ni2+ and Co2+ activate two or more signal transduction pathways in endothelial cells. We clearly showed that there is one pathway in which H-7 and H-8 sensitive protein kinases are involved and a second pathway leading to NF-kappaB activation, which is insensitive to H-7 and H-8. Our results demonstrate that heavy metal ions induce mechanisms of gene activation in endothelial cells as do proinflammatory mediators, indicating that corroding metal ion containing biomaterials can provoke inflammatory reactions by known, as well as by yet unknown, intracellular signaling pathways.
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PMID:Mechanisms of cell activation by heavy metal ions. 1088 Jan

Treatment of HeLa cells or human skin fibroblast cells with hemin led to a time- and dose-dependent rapid induction of c-fos mRNA. This induction was absent in the cells treated with actinomycin D, indicating that the c-fos induction by hemin occurs at the level of transcription. Metalloporphyrins, including zinc-, cobalt-, and tin-protoporphyrin, ferric ion, and protoporphyrin also induced c-fos mRNA. Transient reporter assay with the reporter constructs of the human c-fos gene promoter up to -404 bp connected to the luciferase gene showed high activity but no induction by hemin, suggesting that cis-acting elements, including the serum response element located about -310 bp upstream of the human c-fos gene promoter, may not contribute to the heme-dependent induction. With in-gel assay of protein kinases, the activity of the mitogen-activated protein (MAP) kinases such as extracellular signal-regulated kinase 12 or p38 MAP kinase in hemin-treated HeLa cells was not stimulated. Stimulation of c-Jun N-terminal kinase by hemin was nil. Furthermore, PD58059 and SB203580, inhibitors for MAP kinases, did not affect the hemin-dependent c-fos induction. Of the inhibitors for protein kinases so far tested, KN-62, a specific inhibitor for calmodulin-dependent protein kinase II (CaMK II), inhibited the induction of c-fos mRNA by hemin. Phosphorylation of CaMK II in hemin-treated cells increased. With gel mobility assay, the DNA AP-1 binding activity transiently increased when treating HeLa cells with hemin. Therefore, induction of c-fos led to an activation of AP-1 in the presence of hemin. We suggest that calmodulin-dependent protein kinase II rather than the MAP kinase family regulates the induction of the human c-fos gene expression by hemin.
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PMID:MAP kinase-independent induction of proto-oncogene c-fos mRNA by hemin in human cells. 1038 81

The electrophysiological properties of anterior pituitary somatotropes integrally involve the function of voltage-gated K+ currents. In this study, we have used GH4C1 cell lines to investigate the effect of human GHRH on voltage-gated K+ currents. Because of a clear 'rundown' of the K+ current with classic whole cell recording (WCR) without ATP in pipette solution, nystatin-perforated WCR was the major recording configuration used. Using a low Ca2+ (0.5 mM) bath solution containing Co2+ (1 mM) and TTX (1 microM), GH4 cells predominantly exhibited an outward delayed rectifier K+ current (IK). Local application of growth hormone releasing hormone (GHRH) (100 nM) reversibly reduced the amplitude of the K+ currents (to 83% of control). There was no effect of GHRH on the activation curve of the K+ current and no difference observed using 2.5 mM Ca2+ or low Ca2+ (0.5 mM Ca2++1 mM Co2+) bath solutions. Under the condition of low Ca2+ bath solution, the application of apamin (1 microM) or charybdotoxin (1 microM), two specific blockers of the Ca2+-activated K+ current, did not alter the K+ current or the response to GHRH. This reduction in the K+ current by GHRH was also observed with classic WCR with a pipette solution containing ATP (2 mM). The GHRH-induced reduction in the K+ current was completely abolished by the presence of GDP-beta-s (500 microM) in the pipette solution or by addition of PKC inhibitors, calphostin C (100 nM) and chelerythrine (1 microM), in bath solution. Inhibitor for cAMP-PKA system (Rp-cAMP and H89) did not affect the K+ current response to GHRH. These results suggest that GHRH reduces the voltage-gated K+ current in GH4C1 cells, a response that is mediated by G-proteins and PKC system but not by cAMP-PKA system. The reduction in the K+ current may partially contribute to the GHRH-stimulated growth hormone (GH) secretion.
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PMID:Growth hormone-releasing hormone decreases voltage-gated potassium currents in GH4C1 cells. 1071 10

To identify the signaling pathway that mediates the adrenergic stimulation of the expression of the gene for vascular endothelial growth factor (VEGF) during physiologically induced angiogenesis, we examined mouse brown adipocytes in primary culture. The endogenous adrenergic neurotransmitter norepinephrine (NE) induced VEGF expression 3-fold, in a dose- and time-dependent manner (EC(50) approximately 90 nm). Also, the hypoxia-mimicking agent cobalt, as well as serum and phorbol ester, induced VEGF expression, but the effect of NE was additive to each of these factors, implying that a separate signaling mechanism for the NE-mediated induction was activated. The NE effect was abolished by propranolol and mimicked by isoprenaline or BRL-37344 and was thus mediated via beta-adrenoreceptors. The NE-induced VEGF expression was fully cAMP mediated, an effect which was inhibited by H-89 and thus was dependent on protein kinase A activity. Involvement of other adrenergic signaling pathways (alpha(1)-adrenoreceptors, Ca(2+), protein kinase C, alpha(2)-adrenoreceptors, and pertussis toxin-sensitive G(i)-proteins) was excluded. The specific inhibitor of Src tyrosine kinases, PP2, markedly reduced the stimulation by NE, which demonstrates that a cAMP-dependent Src-mediated pathway is positively connected to VEGF expression. However, inhibition of Erk1/2 MAP kinases by PD98059 was without effect. NE did not prolong VEGF mRNA half-life and its effect was thus transcriptional, and was independent of protein synthesis. These results demonstrate that adrenergic stimulation, through beta-adrenoreceptor/cAMP/protein kinase A signaling, recruits a pathway that branches off from the NE-activated Src-Erk1/2 cascade to enhance transcription of the VEGF gene.
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PMID:Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a beta -adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. 1078 2

The effects of amphetamine on potential changes in both vertebrate and invertebrate central neurons and factors affecting the potential changes were tested. The animals studied included mice, newborn rat and African snail. Seizure was elicited after lethal doses of d-amphetamine (75 mg/kg, i.p.) administration in mice. Repetitive firing of the action potentials were elicited after d-amphetamine (1-30 microM) administration in thin thalamic brain slices of newborn rat. Bursting firing of action potentials in the giant African central RP4 neuron were also elicited after d-amphetamine or l-amphetamine (0.27 mM) administration. The amphetamine elicited bursting firing of action potentials was not blocked even after high concentrations of d-tubocurarine, atropine, haloperidol, hexamethonium administration. Therefore, the amphetamine elicited potential changes may not be directly related to the activation of the receptors of the neuron. The bursting firing of action potentials elicited by amphetamine occurred 20-30 min after amphetamine administration extracellularly, even after high concentrations of d-amphetamine administration (0.27, 1 mM). However, the bursting firing of potentials occurred immediately if amphetamine was administrated intracellularly at lower concentration. Extracellular application of ruthenium red, the calcium antagonist, abolished the amphetamine elicited bursting firing of action potentials. If intracellular injection of EGTA, a calcium ion chelator, or injection with high concentrations of magnesium, the bursting firing of potentials were immediately abolished. These results suggested that the active site of amphetamine may be inside of the neuron and the calcium ion in the neuron played an important role on the bursting of potentials. In two-electrode voltage clamped RP4 neuron, amphetamine, at 0.27 mM, decreased the total inward and steady outward currents of the RP4 neuron. d-Amphetamine also decreased the calcium, Ia and the steady-state outward currents of the RP4 neuron. Besides, amphetamine elicited a negative slope resistance (NSR) if membrane potential was in the range of -50 to -10 mV. The NSR was decreased in cobalt substituted calcium free and sodium free solution. The effects of secondary messengers on the amphetamine elicited potential changes were tested. The bursting firing of action potentials elicited by amphetamine in central snail neurons decreased following extracellular application of H8 (N-(2-methyl-amino) ethyl-3-isoquinoline sulphonamide dihydrochloride), a specific protein kinase A inhibitor and anisomycin, a protein synthesis inhibitor. However, the bursting firing of action potentials were not affected after extracellular application of H7 (1,(5-isoquinolinesulphonyl)-2-methylpiperasine dihydrochloride), a specific protein kinase C (PKC) inhibitor, or intracellular application of GDPbetaS, a G protein inhibitor. The oscillation of membrane potential of the bursting activity was blocked after intracellular injection of 3'-deoxyadenosine, an adenylyl-cyclase inhibitor. These results suggested that the bursting firing of action potentials elicited by d-amphetamine in snail neuron may be associated with the cyclic AMP second messenger system; on the other hand, it may not be associated with the G protein and protein kinase C activity. It is concluded that amphetamine elicited potential changes in both vertebrate and invertebrate central neurons. The changes are closely related to the ionic currents and second messengers of the neurons.
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PMID:Amphetamine elicited potential changes in vertebrate and invertebrate central neurons. 1103 52

We revealed activation of apoptotic signal 1-regulating protein kinase, inhibition of poly-(ADP-ribose) polymerase, and intensification of internucleosomal DNA fragmentation in rat liver during oxidative stress induced by cobalt chloride.
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PMID:Activities of apoptotic signal 1-regulating protein kinase and poly-(ADP-ribose) polymerase and internucleosomal DNA fragmentation in rat liver during oxidative stress induced by cobalt chloride. 1139 89

Ascorbate modulates IK(V) of ON-type mixed rod/cone bipolar cells (Mb) in the goldfish retinal slice through a dopamine D1/G-protein/PKA-coupled mechanism. We investigated the effects of dopamine depletion with intraocular injections of 6-OHDA on IK(V) and its modulation by ascorbate over 1-7 weeks following 6-OHDA treatment. Dopamine depletion was verified by tyrosine hydroxylase immunocytochemistry. Slices were perfused in a saline containing 200 microM sodium ascorbate. One-second puffs of ascorbate-free saline (zero [AA]o), delivered through a 2-3 microm diameter pipette, were directed at the bipolar cells. IK(V) was recorded by conventional whole-cell patch-clamp methods. In normal retinas, puffs of zero [AA]o caused a rapid (<100 ms) suppression of IK(V) of about 50% that lasted for several minutes. This effect was blocked by 1 microM SCH23390 and was unaffected by 2 mM Co2+ or 5 microM spiperone. 6-OHDA treatment resulted in major effects. First, IK(V) was reduced by approximately 50% for weeks 1-6, recovering to a 20% reduction by week 7. Second, puffs of zero [AA]o enhanced IK(V) rather than suppressed it. The enhancement was blocked by SCH23390 and the PKA inhibitor, Wiptide, but was insensitive to spiperone. Third, all parts of the Mb bipolar cell (except for the axon) were sensitive to puffs of zero [AA]o in both normal and 6-OHDA-treated retinas. Fourth, bath application of 20 microM dopamine restored the amplitude of IK(V) but did not reverse the effects of puffed zero [AA]o. IK(V) was fit by two exponentials; all of the effects on IK(V) were on the amplitude of the components and not on the time constants. Chronic dopamine depletion caused reversible changes in the properties of K+ channels underlying IK(V), as well as a long-term change in the intracellular coupling mechanisms between D1-receptor activation and the modulation of IK(V).
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PMID:Dopamine depletion with 6-OHDA enhances dopamine D1-receptor modulation of potassium currents in retinal bipolar cells. 1141 6

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4-7-fold with a K(0.5) of approximately 50 nM. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.
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PMID:Neurotensin regulates DARPP-32 thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors. 1206 80


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