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)

Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla. 131 78

A potent inhibitor of protein kinase C (PKC), inhibitor protein-1 (KCIP-1), isolated from sheep brain has been shown to consist of eight isoforms by reverse-phase HPLC. Direct protein sequence analysis has revealed these to be the same as those of 14-3-3 protein, described as an activator of tyrosine and tryptophan hydroxylases involved in neurotransmitter biosynthesis. The N-termini of KCIP-1 isoforms were shown to be acetylated, and secondary structure predictions revealed a high degree of alpha-helix with an amphipathic nature. KCIP-1 showed no inhibitory activity towards protein kinase M (the catalytic fragment of PKC) and had no effect on the activities of three other protein kinases, cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase II and casein kinase 2. Four forms of KCIP-1 were shown to be substrates for PKC in vitro, but none were phosphorylated by the other protein kinases mentioned above.
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PMID:Multiple isoforms of a protein kinase C inhibitor (KCIP-1/14-3-3) from sheep brain. Amino acid sequence of phosphorylated forms. 131 96

LLC-PK1/PKE20 cells (a continuous epithelial cell line) has two different Na/H exchange activities: Na/H-1 located in the basolateral membrane and Na/H-2 located in the apical membrane [Casavola et al. (1989) Biochem Biophys Res Commun 165:833-837; Haggerty et al. (1988) Proc Natl Acad Sci USA 86:6797-6801]. In the present report we have studied hormone regulation of these exchange activities by measuring Na-dependent recovery of pHi from an acid load (by using microspectrofluorometry and 2,7-bis(carboxyethyl)-5,6-carboxyfluorescein) in response to activation of regulatory cascades by either pharmacological agents or by vasopressin or calcitonin. Agents leading to activation of protein kinase A (cAMP-dependent), such as forskolin (10 microM), 8-Br-cAMP (0.25 mM), and isobutylmethylxanthine (0.5 mM), inhibited Na/H-2 and Na/H-1 by an average of 49%. Stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate, TPA, 100 nM) inhibited Na/H-2 (by an average of 48%) and stimulated Na/H-1 (by an average of 38%); these effects of TPA were also observed in the presence of forskolin (100 microM). Addition of either vasopressin (2 microM) or calcitonin (0.3 microM) onto both sides of the monolayer decreased the activity of Na/H-2 by an average of 26.3% and 27.7% respectively, and stimulated the activity of Na/H-1 by an average of 17.4% and 38.7% respectively; exposure of cells to either hormone stimulated production of cAMP and inositol trisphosphate, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polarized expression of Na+/H+ exchange activity in LLC-PK1/PKE20 cells: II. Hormonal regulation. 131 51

The in vitro expression of bovine leukemia virus (BLV) in short-term cultured bovine peripheral blood mononuclear cells (PBMC) is associated with increased spontaneous lymphocyte blastogenesis. The purpose of this study was to determine whether intracellular pathways responsible for antigen- or mitogen-induced lymphocyte blastogenesis were also responsible for induction of BLV expression. The protein kinase C (PKC) inhibitor 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine dihydrochloride (3-methyl H7) decreased blastogenesis in a dose-dependent manner, as measured by [3H]thymidine incorporation, in unstimulated, lipopolysaccharide-stimulated and phorbol ester (PMA)-stimulated BLV-infected PBMC. Similarly, 3-methyl H7 decreased BLV expression, as measured by production of gp51 envelope antigen or p24gag antigen, in BLV-infected PBMC under the same conditions. Using an RNase protection assay, the inhibition of BLV expression by 3-methyl H7 was shown to be due to decreased transcriptional activity. The cyclic GMP-dependent protein kinase and cyclic AMP-dependent protein kinase inhibitor N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004) did not inhibit either BLV expression or blastogenesis of BLV-infected bovine PBMC. Additional evidence for the PKC-dependent expression of BLV was obtained by using a persistently BLV-infected B-lymphocyte cell line, NBC-13. Activation of PKC by PMA in NBC-13 cells increased BLV expression. 3-methyl H7 decreased the PMA-induced expression of BLV in NBC-13 cells in a dose-dependent manner, whereas HA1004 did not inhibit this expression. These results identify a mechanism for the induction of BLV expression through PKC activation and therefore indicate that latency and replication of BLV is controlled by normal B-lymphocyte intracellular signaling pathways.
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PMID:Inhibition of protein kinase C results in decreased expression of bovine leukemia virus. 131 12

The role of intracellular cAMP and protein kinase A in dopamine-induced inhibition of dopamine neurons and the attenuation of this inhibition by neurotensin were studied in rat midbrain slices. Spontaneous activity of dopamine cells was recorded extracellularly from both the ventral tegmental area and the substantia nigra. Perfusion of the slices with 8-bromo-cAMP and forskolin significantly attenuated dopamine-induced inhibition, but neither blocked the inhibition completely. Neither SQ22536, an inhibitor of adenylate cyclase, nor H8, an inhibitor of protein kinase A, mimicked the inhibitory effect of dopamine on dopamine neurons, although they potentiated dopamine's effect. These results indicate that dopamine-induced inhibition of dopamine neurons can be affected by intracellular cAMP levels, but is unlikely to be mediated solely by inhibition of adenylate cyclase. The similarities between the effects of neurotensin and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP may be involved in the actions of neurotensin. This suggestion is supported by our findings that isobutyl-methylxanthine (an inhibitor of phosphodiesterases) potentiated the effect of neurotensin and SQ22536 and H8 antagonized it. Phorbol-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin.
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PMID:Roles of intracellular cAMP and protein kinase A in the actions of dopamine and neurotensin on midbrain dopamine neurons. 131 60

Voltage-gated Na+ channels, which are responsible for the generation of action potentials in brain, are phosphorylated by cAMP-dependent protein kinase in vitro and in intact neurons. Phosphorylation by cAMP-dependent protein kinase reduces peak Na+ currents 40%--50% in membrane patches excised from rat brain neurons or from CHO cells expressing type IIA Na+ channels. Inhibition of basal cAMP-dependent protein kinase activity by transfection with a plasmid encoding a dominant negative mutant regulatory subunit increases Na+ channel number and activity, indicating that even the basal level of kinase activity is sufficient to reduce Na+ channel activity significantly. Na+ currents in membrane patches from kinase-deficient cells were reduced up to 80% by phosphorylation by cAMP-dependent protein kinase. These effects could be blocked by a specific peptide inhibitor of cAMP-dependent protein kinase and reversed by phosphoprotein phosphatases. Convergent modulation of brain Na+ channels by neurotransmitters acting through the cAMP and protein kinase C signaling pathways may result in associative regulation of electrical activity by different synaptic inputs.
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PMID:Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. 131 85

Uterine arterial blood flow and uterine arterial diameter are known to increase dramatically and progressively throughout gestation. Previous data from our laboratory have demonstrated that the KCl-induced membrane depolarization of uterine arterial smooth muscle specifically induces Ca2+ uptake through the potentially sensitive channels (PSC). Evidence from other laboratories suggests that calcium uptake through the PSC mediates long-term changes in uterine arterial diameter and flow (tone), possibly through activation of protein kinase C (PKC). In study 1 we evaluated uterine arteries removed from gilts on Days 20, 50, 80, and 110 of gestation for their ability to take up extracellular Ca2+ and to contract in response to a depolarizing dose of KCl. The ability of KCl to induce contraction of uterine arteries as well as its ability to stimulate extracellular 45Ca2+ uptake by these same arteries declines (p less than 0.01) progressively from Day 20 through Day 110 of gestation. Estrogen concentrations in systemic blood were negatively correlated with the contractile response (r = -0.57; p less than 0.01) and extracellular 45Ca2+ uptake (r = -0.93; p less than 0.0001) of uterine arteries during gestation. In study 2 we evaluated changes in uterine arterial PKC and protein kinase M (PKM) throughout the estrous cycle and gestation. It was determined that cytosolic PKC declined with the advancement of gestation whereas PKM progressively increased (r = -0.63; p less than 0.01). These data suggest a decreasing ability of the uterine artery to take up extracellular Ca2+ through the PSC as gestation advances, in association with decreasing cytosolic PKC.
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PMID:Evidence for declining extracellular calcium uptake and protein kinase C activity in uterine arterial smooth muscle during gestation in gilts. 131 52

Human alpha-thrombin and histamine each stimulates protein phosphorylation in human umbilical vein endothelial cells (HUVEC). We have identified the most prominent of these phosphoproteins by immunoprecipitation as the human homolog of the widely distributed myristoylated alanine-rich C-kinase substrate (MARCKS). Stimulation by 0.1-10 U/ml of alpha-thrombin produces a time-dependent, sustained (plateau 3-5 min) level of MARCKS phosphorylation. MARCKS phosphorylation requires thrombin catalytic activity but not receptor binding and is also seen in response to stimulation by a peptide, TR (42-55), that duplicates a portion of the thrombin receptor tethered ligand created by thrombin proteolytic activity. One micromolar histamine, like alpha-thrombin, produces sustained phosphorylation of MARCKS (plateau 3-5 min). In contrast, 100 microM histamine results in rapid but transient MARCKS phosphorylation (peak 1-3 min). HUVEC treated with 100 microM histamine for 5 min can be restimulated by alpha-thrombin but not fresh histamine, suggesting that the histamine receptor was desensitized. MARCKS phosphorylation can also be induced by several exogenous protein kinase C (PKC) activators and both alpha-thrombin- and histamine-induced MARCKS phosphorylation are inhibited by the PKC antagonist staurosporine. However, while prolonged PMA pretreatment ablates histamine-induced MARCKS phosphorylation, the ability of thrombin to induce MARCKS phosphorylation is retained. These findings provide evidence for agonist-specific pathways of protein kinase activation in response to thrombin and histamine in HUVEC.
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PMID:Thrombin and histamine rapidly stimulate the phosphorylation of the myristoylated alanine-rich C-kinase substrate in human umbilical vein endothelial cells: evidence for distinct patterns of protein kinase activation. 132 36

The present study was performed to investigate the regulation of cytosolic pH (pHi) and DNA synthesis by parathyroid hormone(PTH) and PTH-related peptide (PTHrP) in osteoblasts, using osteoblastic osteosarcoma cells, UMR-106 which possessed PTH-responsive dual signal transduction systems (cAMP-dependent protein kinase (PKA) and calcium/protein kinase C [Ca/PKC]) and amiloride-inhibitable Na+/H+ exchange system. Both human (h)PTH-(1-34) and hPTHrP-(1-34) caused a progressive decrease in pHi and the inhibition of [3H]thymidine incorporation (TdR) to the same degree in a dose-dependent manner with a minimal effective dose of 10(-10) M. Dibutyryl cAMP (10(-4) M and Sp-cAMPS (10(-4) M), a direct stimulator of PKA also caused a progressive decrease in pHi, and calcium ionophores (A23187 and ionomycin, 10(-6) M) caused a transient decrease in pHi. Pretreatment with amiloride (0.3 mM) mostly blocked dbcAMP- and Sp-cAMPS-induced decrease in pHi but did not affect calcium ionophore-induced decrease in pHi. In the presence of amiloride, PTH and PTHrP caused a transient decrease in pHi, which was similar to the pattern of calcium ionophore-induced change in pHi. Amiloride did not affect the inhibition of TdR by PTH or PTHrP as well as that by cAMP analogues or calcium ionophores. The present study indicated that PTH and PTHrP caused cytosolic acidification through PKA-inhibited Na+/H+ exchange and increased cytosolic calcium-induced pathway and that the regulation of DNA synthesis by PTH and PTHrP was not via Na+/H+ exchange system.
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PMID:Second messenger signaling in the regulation of cytosolic pH and DNA synthesis by parathyroid hormone (PTH) and PTH-related peptide in osteoblastic osteosarcoma cells: role of Na+/H+ exchange. 132 38

The modulation of ion transport pathways in filter-grown monolayers of the Cl(-)-secreting subclone (19A) of the human colon carcinoma cell line HT-29 by muscarinic stimulation was studied by combined Ussing chamber and microimpalement experiments. Basolateral addition of 10(-4) M carbachol induced a complex poly-phasic change of the cell potential consisting of (i) a fast and short (30-sec) depolarization of 15 +/- 1 mV from a resting value of -52 +/- 1 mV and an increase of the fractional resistance of the apical membrane (first phase), (ii) a repolarization of 22 +/- 1 mV leading to a hyperpolarization of the cell (second phase), (iii) a depolarization of 11 +/- 1 mV and a decrease of the fractional resistance of the apical membrane (the third phase), (iv) and sometimes, a hyperpolarization of 6 +/- 1 mV and an increase of the fractional resistance of the apical membrane (fourth phase). The transepithelial potential increased with a peak value of 2.4 +/- 0.3 mV (basolateral side positive). The transepithelial PD started to increase (serosa positive), coinciding with the start of the second phase of the intracellular potential change, and continued to increase during the third phase. Ion replacements and electrical circuit analyses indicate that the first phase is caused by increase of the Cl- conductance in the apical and basolateral membrane, the second phase by increased K+ conductance of the basolateral membrane, and the third phase and the fourth phase by increase and decrease, respectively, of an apical Cl- conductance. The first and second phase of the carbachol effect could be elicited also by ionomycin. They were strongly reduced by EGTA. Phorbol dibutyrate (PDB) induced a sustained depolarization of the cell and a decrease of the apical fractional resistance. The results suggest that two different types of Cl- channels are involved in the carbachol response: one Ca2+ dependent and a second which may be PKC sensitive. In the presence of a supramaximal concentration of forskolin, carbachol evoked a further increase of the apical Cl- conductance. It is concluded that the short-lasting carbachol/Ca(2+)-dependent Cl- conductance is different from the forskolin-activated conductance. The increase of the Cl- conductance in the presence of forskolin by carbachol may be due to activation of different Cl- channels or to modulation of the PKA-activated Cl- channels by activated PKC.
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PMID:Biphasic increase of apical Cl- conductance by muscarinic stimulation of HT-29cl.19A human colon carcinoma cell line: evidence for activation of different Cl- conductances by carbachol and forskolin. 132 Jul


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