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 adenosine A2a receptor inhibition of potassium (15 mM)-evoked GABA release from striatal nerve terminals has been examined. High extracellular calcium concentrations (4 mM) reduced the effect of the A2a receptor agonist CGS-21680 (1 nM). CGS-21680 inhibited GABA release in the presence of the L-type calcium channel blocker nifedipine, which itself inhibited evoked GABA release (by 16 +/- 4%). omega-Conotoxin inhibited the evoked release by 45 +/- 4% and prevented the action of CGS-21680. Forskolin and 8-bromo cyclic AMP both stimulated evoked GABA release at low concentrations, but at higher concentrations they abolished the inhibition by CGS-21680 without affecting the evoked release. The nonselective protein kinase inhibitor H-7 inhibited both the evoked release and the inhibition by CGS-21680, whereas the selective protein kinase A and G inhibitor HA-1004 had no effect on either evoked release or the action of CGS-21680. Pretreatment with pertussis toxin did not affect the A2a receptor-mediated inhibition. Therefore, the effect of A2a receptor stimulation was not mediated by protein kinases A or G but was inhibited by elevated cyclic AMP levels and mimicked by inhibitors of the N-type calcium channel and protein kinase C.
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PMID:Inhibition of striatal GABA release by the adenosine A2a receptor is not mediated by increases in cyclic AMP. 776 61

We characterized Ca2+ entry in rat aortic smooth muscle cells (SMCs) maintained in primary culture by measuring uptake of 45Ca2+ or Mn2+ from a normal balanced salt solution and the extracellular Ca(2+)-induced increase in the intracellular Ca2+ concentration ([Ca2+]i) in a medium [high pH (pH 8.8)/high Mg2+ (20 mM) medium containing a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin] that inhibits removal of Ca2+ from the cytoplasm. Such measurements in the presence or absence of a dihydropyridine (DHP) calcium channel antagonist (PN200-110) or hyperpolarizing agent (valinomycin) revealed that DHP-sensitive voltage-gated Ca2+ channels (VGCCs) are activated in these SMCs under resting conditions and that DHP-sensitive Ca2+ entry occurs mostly via these VGCCs. We found that receptor stimulation by endothelin-1 in these SMCs resulted in activation of neither DHP-sensitive nor -insensitive Ca2+ entry, but rather resulted in marked suppression of the former. Utilizing the DHP-sensitive extracellular Ca(2+)-induced increase in [Ca2+]i as a monitor of activity of the DHP-sensitive VGCCs, we investigated the effects of protein kinase activators and phosphatase inhibitors on the regulation of these VGCCs. We found that the DHP-sensitive VGCCs were inhibited by endothelin-1 through the activation of protein kinase C. We also found that they were inhibited by 8Br-cGMP, okadaic acid, and calyculin A.
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PMID:Regulation of Ca2+ entry in rat aortic smooth muscle cells in primary culture. 782 43

Dose- and time-dependent killing of cultured rat hepatocytes was produced by aluminum maltolate (AlM), a neutral, water-soluble complex of aluminum 3-hydroxy-2-methyl-4H-pyran-4-one. Treatment with 10 mM AlM for 1 h killed 50% or more of the cells within 3 h. Removal of calcium from the culture medium or treatment with calcium channel blockers (verapamil, nifedipine, diltiazem) potentiated the cell killing. By contrast, inhibition by thapsigargin of the sequestration of intracellular calcium by the endoplasmic reticulum reduced the toxicity of AlM. In turn, activation of protein kinase C with 12-O-tetradecanoylphorbol 13-acetate or activation of protein kinase A with 8-[4-chlorophenyl-thio]adenosine 3',5'-cyclic monophosphate also reduced the toxicity of AlM. By contrast, inhibition of protein kinase activity by staurosporine potentiated the cell killing. Staurosporine, however, did not reverse the protection afforded by thapsigargin. Hepatocytes treated with AlM for 1 h were rescued by adding deferoxamine as late as 90 min following the removal of AlM, whereas pretreatment for 1 h with deferoxamine did not prevent the toxicity of AlM. ATP depletion did not precede loss of viability. Pharmacologic probes excluded oxidative stress as a mechanism of lethal injury by AlM, and inhibition of protein synthesis by cycloheximide did not protect the hepatocytes, thereby excluding activation of a cell death program. These data define a new model in which aluminum kills liver cells by a mechanisms distinct from previously recognized pathways of lethal cell injury. It is hypothesized that aluminum binds to cytoskeletal proteins intimately associated with the plasma membrane. This interaction eventually disrupts the permeability barrier function of the cell membrane, an event that heralds the death of the hepatocyte. The intracellular calcium ion concentration and protein phosphorylation may modify the interaction of aluminum with its critical targets. Alternatively, aluminum may inhibit the phosphorylation of cytoskeletal elements, thereby interfering with their function.
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PMID:The absence of extracellular calcium potentiates the killing of cultured hepatocytes by aluminum maltolate. 784 Jun 48

The protein kinase C activator phorbol 12,13-dibutyrate (0.5 microM, PDBu) and the protein kinase A activator forskolin (20 microM) each increased evoked monosynaptic inhibitory postsynaptic current (IPSC) amplitude, without affecting its reversal potential, and increased the frequency of miniature IPSCs (mIPSCs), without affecting their amplitude or kinetics, as assessed with whole-cell recording form CA3 pyramidal cells in hippocampal slice cultures. The effects of forskolin and PDBu on both evoked IPSC amplitude and mIPSC frequency were additive and were antagonized by inhibitors of protein kinases A and C, respectively. The kinase activator-induced increases in mIPSC frequency were quantitatively comparable to the increases in evoked IPSC amplitude. The increases in mIPSC frequency were not attenuated by the voltage-dependent calcium channel blocker Cd2+ (100 microM). We conclude that stimulation of protein kinases A and C potentiates hippocampal inhibitory synaptic transmission through independent presynaptic mechanisms of action. Kinase-induced potentiation of spontaneous release does not require modulation of axon terminal Ca2+ channels. This mechanism may also contribute substantially to the potentiation of evoked release.
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PMID:Presynaptic enhancement of inhibitory synaptic transmission by protein kinases A and C in the rat hippocampus in vitro. 786 96

The effect of pure pressure without shear stress or stretch on the release of endothelin-1 was investigated. Elevation of pressure significantly enhanced endothelin-1 release from cultured human umbilical vein endothelial cells. A calcium channel blocker, nifedipine, and a putative stretch-activated channel blocker, gadolinium, did not affect the pressure-induced endothelin-1 increase. On the other hand, a phospholipase C inhibitor, 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, and protein kinase C inhibitors, 1-5-(isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine, significantly inhibited the pressure-induced endothelin-1 increase. Moreover, pure pressure reduced basal nitric oxide release, while pretreatment with a nitric oxide synthase inhibitor, NG-monomethyl-L-arginine, had no effect on the pressure-induced endothelin-1 increase. In conclusion, our results show for the first time that pressure enhances endothelin-1 release partially through activation of phospholipase C and protein kinase.
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PMID:Pressure enhances endothelin-1 release from cultured human endothelial cells. 787 71

Calcium entry into excitable cells through voltage-gated calcium channels can be influenced by both the rate and pattern of action potentials. We report here that a cloned neuronal alpha 1C L-type calcium channel can be facilitated by positive pre-depolarization. Both calcium and barium were effective as charge carriers in eliciting voltage-dependent facilitation. The induction of facilitation was shown to be independent of intracellular calcium levels, G-protein interaction and the level of phosphatase activity. Facilitation was reduced by the injection of inhibitors of protein kinase A and required the coexpression of a calcium channel beta subunit. In contrast, three neuronal non-L-type calcium channels, alpha 1A, alpha 1B and alpha 1E, were not subject to voltage-dependent facilitation when coexpressed with a beta subunit. The results indicate that the mechanism of neuronal L-type calcium channel facilitation involves the interaction of alpha 1 and beta subunits and is dependent on protein kinase A activity. The selective voltage-dependent modulation of L-type calcium channels is likely to play an important role in neuronal physiology and plasticity.
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PMID:Voltage-dependent facilitation of a neuronal alpha 1C L-type calcium channel. 795 69

In vascular smooth muscle (VSM) cells, the slow inward calcium current (ICa) may be regulated by phosphorylation of the calcium channel protein or of associated regulatory proteins. We investigated the role of several protein kinase systems in the regulation of ICa in cultured A7r5 cells, a clonal cell line derived from rat aorta. The perforated-patch voltage-clamp technique was used to record whole cell ICa. To isolate the ICa, the pipette contained high Cs+ and the bath contained 140 mM tetraethylammonium to block potassium currents. Ba2+ was used as the charge carrier. In control experiments, ICa was stable for at least 15 min. Compared with 23 +/- 3% in the time-control group (i.e., run-down; n = 10), 3 mM 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP) inhibited peak ICa by 53 +/- 3% (n = 9) within 15 min. Similarly, 3 mM 8-bromo-guanosine 3',5'-cyclic monophosphate (8-BrcGMP) inhibited ICa by 59 +/- 4 (n = 11). Application of 30 microM forskolin inhibited ICa by 58 +/- 9% (n = 6) within 5 min (compared with 4 +/- 3% for the 5-min time control). Forskolin also shifted the reversal potential to the left, suggesting a stimulation of an outward current. In the presence of the protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, the same dose of forskolin had no effect (n = 7). The water-soluble analogue of forskolin (L-858051, 30 microM) decreased ICa by 72 +/- 11% (n = 9) and reduced the outward current component.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of calcium channel current in A7r5 vascular smooth muscle cells by cyclic nucleotides. 802 95

Early glucocorticoid feedback in sheep anterior pituitary (AP) cells was compared and contrasted with that in mouse pituitary tumor AtT-20 cells. Dexamethasone (DEX) inhibited corticotropin-releasing hormone (CRH)-stimulated adrenocorticotropin (ACTH) release in a concentration- and time-dependent manner with similar potency amongst cell types. This inhibition was mediated through type II glucocorticoid receptors and required the synthesis of new protein. However, stimulation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) resulted in greater ACTH release and greater inhibition by DEX in sheep AP cells. In contrast to sheep AP cells, AtT-20 cells were insensitive to glucocorticoids when secretion was stimulated by KCl depolarization or the voltage-dependent calcium channel agonist, maitotoxin (MTX). In both cell types, CRH-, KCl-, and MTX-stimulated ACTH release was inhibited by the calcium channel blocker, nifedipine (NIF). Whereas NIF also inhibited PMA-induced ACTH secretion in AtT-20 cells, it did not in sheep AP cells. These data demonstrate that early glucocorticoid feedback is operative in sheep corticotrophs and that AtT-20 cells appear to serve as an appropriate mechanistic model for aspects of negative feedback when the CRH-protein kinase A pathway is activated but may not be appropriate when ACTH secretion is activated via other intracellular signaling pathways.
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PMID:Glucocorticoid negative feedback in sheep corticotrophs: a comparison with AtT-20 corticotroph tumor cells. 806 55

Two size forms of the class B N-type calcium channel alpha 1 subunit were recently identified with CNB1, an antipeptide antibody directed against an intracellular loop of this channel (Westenbroek, R.E., Hell, J.W., Warner, C., Dubel, S.J., Snutch, T.P., and Catterall, W.A. (1992) Neuron 9, 1099-1115). To investigate the biochemical differences between these two size forms, the antibodies CNB3 and CNB4 were raised against peptides with sequences corresponding to the COOH-terminal end of the full-length form. Immunoblot experiments demonstrated that both antibodies specifically recognize the longer form of 250 kDa, indicating that the COOH-terminal regions of the two size forms of the class B N-type channel alpha 1 subunit are different. Phosphorylation experiments with immunopurified calcium channels and different second messenger-activated protein kinases revealed that both the 220- and 250-kDa forms of the class B N-type calcium channel alpha 1 subunit are substrates for cAMP-dependent protein kinase, cGMP-dependent protein kinase, and protein kinase C. These three kinases incorporated approximately 1 mol of phosphate/mol of binding sites for omega-conotoxin (omega-CgTx) GVIA, a ligand specific for the N-type calcium channel, and may regulate the activity of both forms in vivo. In contrast, calcium- and calmodulin-dependent protein kinase II (CaM kinase II) phosphorylated only the long form of the class B N-type calcium channel alpha 1 subunit, with a stoichiometry of 0.5 mol of phosphate/mol of total omega-CgTx GVIA binding sites. Specific phosphorylation of the long form of the class B alpha 1 subunit by CaM kinase II may differentially regulate the function of N-type calcium channels containing different size forms of their alpha 1 subunits in vivo.
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PMID:Differential phosphorylation of two size forms of the N-type calcium channel alpha 1 subunit which have different COOH termini. 812 57

This editorial review focuses on recent observations regarding the mechanism and regulation of calcium transport in hormone-sensitive distal convoluted tubules. Parathyroid hormone (PTH) and calcitonin increase active calcium absorption by distal convoluted tubules. Occupancy of these peptide hormone receptors results in the activation of both protein kinase A and protein kinase C. The inhibition of either kinase blocks calcium transport. The time course of stimulation of calcium entry in distal convoluted tubules by PTH is slow compared with that by calcitonin. The latency associated with PTH action may be due to the induction of protein synthesis. PTH and calcitonin hyperpolarize membrane voltage, which in turn increases calcium entry. Calcium entry is mediated by calcium channels. These channels exhibit a low, single-channel conductance and are sensitive to dihydropyridine-type calcium channel blockers. Unlike L-type calcium channels, the channel open probability of distal convoluted tubule calcium entry channels is increased upon hyperpolarization. This novel combination of properties suggests that the underlying structure of these calcium entry channels may be unique.
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PMID:Hormone-responsive Ca2+ entry in distal convoluted tubules. 816 21


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