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)

Atrial natriuretic peptide (ANP) regulates diverse physiological responses by binding to its specific guanylyl cyclase-A receptor (Npra) which synthesizes the intracellular second messenger cGMP. To understand the molecular mechanisms of cellular signaling of ANP, we have studied its effect on the enzymatic activity of overexpressed protein kinase C (PKC) in murine Leydig tumor (MA-10) cells which were transfected with PKC-alpha cDNA. Treatments with 12-O-tetradecanoylphorbol-13-acetate (TPA), angiotensin II (ANG II) and endothelin-1 (ET-1) stimulated the PKC activity by 4-5-fold in PKC-alpha cDNA transfected MA-10 cells. The pretreatment of PKC-alpha transfected cells with ANP significantly inhibited the TPA-, ANG II- and ET-1-stimulated PKC activity. The agonist-stimulated PKC activity was also inhibited in the presence of 8-bromo-cGMP, however, cAMP had no effect on stimulatory PKC activity. The exposure of cells to Npra- antagonist A71915, which blocks the production of cGMP, significantly reduced the inhibitory effect of ANP on agonist-stimulated PKC activity and accumulation of intracellular cGMP in MA-10 cells. Similarly, inhibition of cGMP-dependent protein kinase by KT5823, restored the stimulatory levels of PKC activity in the presence of ANP. These results provide direct evidence that ANP antagonizes the agonist-stimulated PKC activity in MA-10 cells, involving the specific receptor Npra, its second messenger cGMP and cGMP-dependent protein kinase. Together, these findings implicate that ANP may act as a negative mediator of 'cross-talk' between PKC-alpha and Npra signaling pathway in MA-10 cells.
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PMID:Stimulation of atrial natriuretic peptide receptor/guanylyl cyclase- A signaling pathway antagonizes the activation of protein kinase C-alpha in murine Leydig cells. 915 Feb 79

1. The effects of endothelin-1 (ET-1) on sinoatrial (SA) node preparations of the rabbit heart were studied by means of whole-cell clamp techniques. 2. ET-1 at 1 nM slowed the spontaneous beating activity and rendered half of the cells quiescent. At a higher concentration of 10 nM, the slowing and cessation of spontaneous activity were accompanied by hyperpolarization. 3. In voltage-clamp experiments, ET-1 decreased the basal L-type Ca2+ current (Ica(L)) dose-dependently with a half-maximal inhibitory concentration (EC50) of 0.42 nM and maximal inhibitory response (Emax) of 49.5%. The delayed rectifying K+ current (Ik) was also reduced by 33.2 +/- 11.1% at 1 nM. In addition an inwardly rectifying K+ current was activated by ET-1 at higher concentrations (EC50 = 4.8 nM). These ET-1-induced changes in membrane currents were abolished by BQ485 (0.3 microM), a highly selective ETA receptor antagonist. 4. When Ica(L) was inhibited by ET-1 (1 nM), subsequent application of 10 microM ACh showed no additional decrease in Ica(L), suggesting the involvement of cyclic AMP in the effects of ET-1 on Ica(L). In contrast, 1 nM ET-1 further decreased Ica(L) in the presence of 10 microM ACh, suggesting that ET-1 activates some additional mechanism(s) which inhibit Ica(L). The ET-1-induced Ica(L) inhibition was abolished by protein kinase A inhibitory peptide (PKI, 20 microM) or H-89 (5 microM). However, the Ica(L) inhibition was not affected by methylene blue (10 microM), suggesting a minor role for cyclic GMP in the effect of ET-1 under basal conditions. 5. ET-1 failed to inhibit Ica(L) when the pipette contained GDP beta S (200 microM). However, incubation of the 21.5 +/- 9.5%, whereas it abolished the inhibitory effect of ACh on Ica(L). 6. Intracellular perfusion of 8-bromo cyclicAMP (8-Br cyclicAMP, 500 microM) attenuated, but did not abolish the inhibitory effect of ET-1 on Ica(L). This 8-Br cyclicAMP-resistant component (17.5 +/- 14.4%, n = 20) was not affected by combined application of 8-Br cyclicAMP-bromo cyclicGMP (500 microM), ryanodine (1 microM) or phorbol-12-myristate-13-acetate (TPA; 50 nM). 7. In summary, ET-1 exerts negative chronotropic effects on the SA node via ETA-receptors. ET-1 inhibits both ICa(L) and Ik, and increases background K+ current. The inhibition of ICa(L) by ET-1 is mainly due to reduction of the cyclicAMP levels via PTX-sensitive G protein, but some other mechanism(s) also seems to be operative.
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PMID:Negative chronotropic actions of endothelin-1 on rabbit sinoatrial node pacemaker cells. 931 42

We have previously reported that stretching of cardiomyocytes activates the phosphorylation cascade of protein kinases, including Raf-1 kinase and mitogen-activated protein (MAP) kinases, followed by an increase in protein synthesis partly through enhanced secretion of angiotensin II and endothelin-1. Membrane proteins, such as ion channels and exchangers, have been postulated to first receive extracellular stimuli and evoke intracellular signals. The present study was performed to determine whether mechanosensitive ion channels and exchangers are involved in stretch-induced hypertrophic responses. Neonatal rat cardiomyocytes cultured on expandable silicone dishes were stretched after pretreatment with a specific inhibitor of stretch-sensitive cation channels (gadolinium and streptomycin), of ATP-sensitive K+ channels (glibenclamide), of hyperpolarization-activated inward channels (CsCl), or of the Na+-H+ exchanger (HOE 694). Pretreatment with gadolinium, streptomycin, glibenclamide, and CsCl did not show any inhibitory effects on MAP kinase activation by mechanical stretch. HOE 694, however, markedly attenuated stretch-induced activation of Raf-1 kinase and MAP kinases by approximately 50% and 60%, respectively, and attenuated stretch-induced increase in phenylalanine incorporation into proteins. In contrast, HOE 694 did not inhibit angiotensin II-and endothelin-1-induced Raf-1 kinase and MAP kinase activation. These results suggest that among many mechanosensitive ion channels and exchangers, the Na+-H+ exchanger plays a critical role in mechanical stress-induced cardiomyocyte hypertrophy.
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PMID:Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy. 950 3

Noradrenaline increased the mRNA levels of c-fos and c-jun in rat-1 fibroblast lines stably expressing the cloned alpha1-adrenoceptor subtypes. The efficacy to induce the expression of c-fos mRNA was similar for the three cell lines (alpha1d = alpha1b = alpha1a) but different for c-jun (alpha1a > or = alpha1b > alpha1d). The EC50 values were also different: approximately 5 nM (c-fos) and approximately 300 nM (c-jun) for cells transfected with the alpha1a subtype, approximately 30 nM (c-fos) and approximately 300 nM (c-jun) for cells transfected with the alpha1b subtype and approximately 300 nM (c-fos and c-jun) for those transfected with the alpha1d subtype. Staurosporine and protein kinase C down-regulation blocked such effects, indicating a role of this protein kinase. Endothelin-1 (10 nM) also increased the levels of c-fos and c-jun mRNAs. These actions of endothelin-1 were unaffected by staurosporine and protein kinase C down-regulation. It is concluded that activation of any of the three cloned subtypes can increase the levels of c-fos and c-jun mRNAs and that protein kinase C plays a major role in mediating such effects.
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PMID:Alpha1-adrenoceptor subtype activation increases proto-oncogene mRNA levels. Role of protein kinase C. 954 2

The effects of cAMP on the oxytocin-stimulated increase in phosphatidylinositide turnover and the possible pathways involved were investigated in a human myometrial cell line (PHM1-41) and in COS-M6 cells overexpressing the oxytocin receptor. Preincubation with chlorophenylthio-cAMP (CPT-cAMP), forskolin, or relaxin inhibited oxytocin-stimulated phosphatidylinositide turnover in PHM1-41 cells, and the inhibition was reversed by H-89, a relatively specific protein kinase A inhibitor. Both CPT-cAMP and transiently expressed protein kinase A catalytic subunit inhibited stimulation by oxytocin and carbachol of [3H]inositol 1,3,4-trisphosphate formation in COS-M6 cells expressing oxytocin or muscarinic M1 receptors, respectively. CPT-cAMP also inhibited phosphatidylinositide turnover stimulation by endothelin-1 in PHM1-41 cells, further demonstrating the generality of the cAMP-inhibitory mechanism. Since G betagamma activation of phospholipase Cbeta2 (PLCbeta2) is a suggested target of protein kinase A, the possibility that the oxytocin receptor couples to PLCbeta2 via G alpha(i)G betagamma activation was explored. Western blot analysis of PHM1-41 cells and COS-M6 cells detected PLCbeta1 and PLCbeta3, but not PLCbeta2. In PHM1-41 cells, pertussis toxin reduced the oxytocin-stimulated increase in [3H]inositol 1,3,4-trisphosphate by 53%, and this was reversed completely by H-89. Thus, the inhibitory effect of pertussis toxin may result from an indirect effect of cAMP elevation. These data suggest that receptor/G alpha(q)-coupled stimulation of PLCbeta1 or PLCbeta3 can be inhibited by cAMP through a phosphorylation mechanism involving protein kinase A that does not involve PLCbeta2. In smooth muscle, this mechanism could constitute potentially important cross-talk between pathways regulating contraction and relaxation.
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PMID:Evidence for inhibition by protein kinase A of receptor/G alpha(q)/phospholipase C (PLC) coupling by a mechanism not involving PLCbeta2. 956 32

c-Jun N-terminal protein kinase (JNK) and p38, two distinct members of the mitogen-activated protein (MAP) kinase family, regulate gene expression in response to various extracellular stimuli, yet their physiological functions are not completely understood. In this report we show that JNK and p38 exerted opposing effects on the development of myocyte hypertrophy, which is an adaptive physiological process characterized by expression of embryonic genes and unique morphological changes. In rat neonatal ventricular myocytes, both JNK and p38 were stimulated by hypertrophic agonists like endothelin-1, phenylephrine, and leukemia inhibitory factor. Expression of MAP kinase kinase 6b (EE), a constitutive activator of p38, stimulated the expression of atrial natriuretic factor (ANF), which is a genetic marker of in vivo cardiac hypertrophy. Activation of p38 was required for ANF expression induced by the hypertrophic agonists. Furthermore, a specific p38 inhibitor, SB202190, significantly changed hypertrophic morphology induced by the agonists. Surprisingly, activation of JNK led to inhibition of ANF expression induced by MEK kinase 1 (MEKK1) and the hypertrophic agonists. MEKK1-induced ANF expression was also negatively regulated by expression of c-Jun. Our results demonstrate that p38 mediates, but JNK suppresses, the development of myocyte hypertrophy.
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PMID:Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. 958 92

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Mitogen-activated protein kinases (MAPK) and cAMP are important components of the intracellular signaling pathways. We studied the effects of endothelin-1 (ET-1) and isoproterenol (ISO) on the intracellular cAMP level in human pericardial smooth-muscle cells and investigated how these two ligands regulate the activity of MAPK (p42/p44 MAPK). ET-1 or ET-3 alone did not exhibit any effect on the cAMP level in these cells. In contrast, ISO at 10 microM caused a 12-fold increase in the accumulation of cAMP (370 +/- 70 pmol/ml vs. 31 +/- 5 pmol/ml). Addition of ET-1 attenuated ISO-stimulated cAMP accumulation by 50% in a dose-dependent manner, with an IC50 of 0.12 nM. ET-3 was 100-fold less potent (IC50 = 15 nM). The attenuating effect of ET-1 was completely blocked by 1 microM FR139317, suggesting that the effect is primarily mediated by the ETA receptor. In serum-deprived cells, the basal MAPK activity was low (0.07 +/- 0.01 nmoles Pi/mg/min). Addition of 10 nM ET-1 stimulated MAPK 15-fold within 5 min at 37 degrees C (1.08 +/- 0.02 nmoles Pi/mg/min). ISO alone (10 microM) had no significant effect on MAPK. However, ISO markedly attenuated ET-1-stimulated MAPK activity; a approximately 50% decrease in MAPK activity was observed in the presence of 10 microM ISO. Similar results were obtained when forskolin was tested. The effects of ISO and forskolin on attenuating ET-1-stimulated MAPK activity could be reversed by treating cells with H89, an inhibitor of protein kinase A. These results show that ET-1 partially attenuated the accumulation of cAMP induced by ISO, and that ISO attenuated the MAPK activity induced by ET-1, possibly via activation of protein kinase A. This study suggests that counter-regulation among various ligands and cross-talk among different signaling pathways may be required to modulate biologic functions in a living cell.
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PMID:Endothelin and isoproterenol counter-regulate cAMP and mitogen-activated protein kinases. 959 34

To understand better the function of endothelin-1 (ET-1) in renal physiology, we examined vascular and glomerular expression of ET-1 in normal human kidney and in lupus nephritis. Immunohistochemical analysis revealed that renal endothelium of glomeruli, arteries, veins, and capillaries expressed ET-1. Endothelial cells were the principal source of glomerular ET-1; positive immunostaining was detected only rarely in mesangial cells and vascular smooth muscle cells from normal kidney. However, mesangial staining for ET-1 was elevated in patients with lupus nephritis, suggesting that under certain conditions mesangial cells elaborate ET-1. Indeed cultured human mesangial cells from normal subjects secreted ET-1 peptide. ET-1 secretion was augmented by the protein kinase C activator phorbol ester and by transforming growth factor-beta1 (TGF-beta1), a cytokine implicated in the development of glomerulosclerosis. Transient transfection of cultured mesangial cells with a preproET-1 reporter construct showed that the preproET-1 promoter is transcriptionally active in mesangial cells and is stimulated by TGF-beta1, phorbol ester, or ectopic expression of protein kinase beta1. Cultured human mesangial cells have both ETA and ETB receptors that contribute to ET-1-stimulated mitogenesis. Taken together, these results demonstrate that ET-1 is expressed at sites where paracrine or autocrine signaling by ET-1 might control renal vasoconstriction, glomerular filtration rate, and remodeling of the glomerulus in renal disease.
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PMID:Vascular and glomerular expression of endothelin-1 in normal human kidney. 968 99

Activation of human neutrophil migration by endothelin-1 and endothelin-3 is inhibited by guanylate cyclase inhibitors, by antagonists of protein kinase G (G-kinase), and by KT-5823, an inhibitor of G-kinase. Although no direct effect of endothelins on cGMP level could be established, these results suggest that the effect of these endothelins on migration is mediated by cGMP, and that the effect of cGMP proceeds via a G-kinase. There was little or no effect of guanylate cyclase inhibitors and G-kinase antagonists on endothelin-2-activated migration, indicating that the role of cGMP and G-kinase in endothelin-2-induced activation was either absent or at least different from that of the other endothelins. As compared with other activators, the role of G-kinase in formyl-methionyl-leucyl-phenylalanyl(fMLP-)activated migration resembled that of endothelin-activated migration, while the role of G-kinase in interleukin-8- or leukotriene B4-activated migration was less pronounced.
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PMID:The involvement of protein kinase G in stimulation of neutrophil migration by endothelins. 969 19


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