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)

Endothelin-1 (ET-1) regulates gene expression and growth of vascular cells by triggering signals that link its cognate, G protein-coupled receptor in the plasma membrane to transcriptional activation of immediate early genes in the nucleus. To define the nature of these signals, we asked whether Ras proteins contribute to activation of the c-fos serum response element (SRE) by ET-1 in mesangial cells, a microvascular cell from the renal glomerulus. ET-1 stimulated Ras by increasing Ras GTP loading. Addition of ET-1 or transfection with a plasmid expressing v-Ha-Ras stimulated SRE-dependent transcription. Activation of the c-fos SRE by ET-1 was blocked by a dominant negative Asn-17 c-Ha-Ras mutant. Expression of v-Ha-Ras reversed inhibition of ET-1-stimulated SRE transcriptional activity by Asn-17 c-Ha-Ras. ET-1 also stimulated kinase activity of c-Raf-1, a downstream effector in Ras signaling cascades. Activation of the c-fos SRE by transfection with a plasmid expressing constitutively activated delta Raf-1 was consistent with a role for Ras-Raf-1 in ET-1 signaling. Interestingly, Ras-dependent SRE activation in cells treated with ET-1 was blocked by point mutations in the SRE CArG DNA sequence, which binds the serum response factor, but not by mutations that inhibit binding of ternary complex factors (p62TCF) to the Ets DNA sequence of the SRE. Thus, Ras contributes to a nuclear signaling cascade linking ET-1 receptors to transcriptional activation through the CArG cis-element of the c-fos SRE.
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PMID:Nuclear signaling by endothelin-1. A Ras pathway for activation of the c-fos serum response element. 774 5

The translocation of protein kinase C (PKC) isoforms PKC-alpha, PKC-delta, PKC-epsilon, and PKC-zeta from soluble to particulate fractions was studied in ventricular cardiomyocytes cultured from neonatal rats. Endothelin-1 (ET-1) caused a rapid ETA receptor-mediated translocation of PKC-delta and PKC-epsilon (complete in 0.5-1 min). By 3-5 min, both isoforms were returning to the soluble fraction, but a greater proportion of PKC-epsilon remained associated with the particulate fraction. The EC50 of translocation for PKC-delta was 11-15 nM ET-1 whereas that for PKC-epsilon was 1.4-1.7 nM. Phenylephrine caused a rapid translocation of PKC-epsilon (EC50 = 0.9 microM) but the proportion lost from the soluble fraction was less than with ET-1. Translocation of PKC-delta was barely detectable with phenylephrine. Neither agonist caused any consistent translocation of PKC-alpha or PKC-zeta. Activation of p42 and p44 mitogen-activated protein kinase (MAPK) by ET-1 or phenylephrine followed more slowly (complete in 3-5 min). Phosphorylation of p42-MAPK occurred simultaneously with its activation. The proportion of the total p42-MAPK pool phosphorylated in response to ET-1 (50%) was greater than with phenylephrine (20%). In addition to activation of MAPK, an unidentified p85 protein kinase was activated by ET-1 in the soluble fraction whereas an unidentified p58 protein kinase was activated in the particulate fraction.
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PMID:Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. 780 10

Endothelin-1 is a peptide hormone constitutively secreted by vascular and endocardial endothelial cells. Secretion of endothelin-1 is increased under certain pathophysiological conditions, including coronary vasospasm, cardiac ischaemia and myocardial infarction. We have examined the effect of endothelin-1 on the protein kinase A (PKA)-dependent chloride current in voltage-clamped guinea pig ventricular myocytes. This conductance, induced by catecholamines through beta-adrenergic receptors, counteracts the simultaneously increased L-type calcium current by shortening the action potential duration. We report here that endothelin-1, acting through ETA (endothelin-1-selective) receptors, inhibited the current through a pertussis toxin-sensitive mechanism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help protect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of catecholamines are increased.
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PMID:Inhibition of the cardiac protein kinase A-dependent chloride conductance by endothelin-1. 751 70

Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor yet identified. This peptide plays an important role in the regulation of arterial tone, in part through its interaction with endogenous vasodilator compounds. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs), we determined the effects of prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 on ET-1 synthesis and secretion from cultured bovine aortic endothelial cells and on ET-1 action in aortic smooth muscle cells. Both PGE2 and PGI2 (vasodilator prostaglandins) caused an approximately 40% inhibition of basal ET-1 secretion and a 50% inhibition of serum-stimulated ET-1 secretion in a dose-related and time course fashion. In contrast, the vasoconstrictor prostaglandin, thromboxane A2, had no effect on ET-1 secretion. PGE2 and PGI2 similarly inhibited the basal production of new ET-1 protein (translation) by 40-50% and inhibited the basal steady-state mRNA expression of ET-1 in bovine aortic endothelial cells by 60-70%. Both prostaglandins also caused an approximately 55% inhibition of ET-1 transcription, as shown by chloramphenicol acetyltransferase reporter studies. PGE2 and PGI2 strongly stimulated cGMP generation; both the PG stimulation of cGMP and the inhibition of ET-1 secretion and translation were reversed by LY83583, a general inhibitor of cGMP generation. The PG-induced inhibition of ET-1 secretion and translation was also reversed by KT5823, an inhibitor of cGMP-dependent protein kinase, but not by (Rp)-adenosine cyclic 3':5'-monophosphate, an inhibitor of protein kinase A activation. PGE2 and PGI2 also inhibited both basal and ET-1-stimulated DNA synthesis in aortic smooth muscle cells by approximately 45% through a cGMP-dependent mechanism. Therefore, two endogenous PGs, known to be important vasodilators in vivo, significantly inhibit the transcription, translation, secretion, and action of ET-1. We propose that the vasodilator action of the PGs results, in part, from their ability to inhibit the production of this potent vasoconstrictor.
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PMID:Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells. 816 94

We have recently shown that mechanical stress induces cardiomyocyte hypertrophy partly through the enhanced secretion of angiotensin II (ATII). Endothelin-1 (ET-1) has been reported to be a potent growth factor for a variety of cells, including cardiomyocytes. In this study, we examined the role of ET-1 in mechanical stress-induced cardiac hypertrophy by using cultured cardiomyocytes of neonatal rats. ET-1 (10(-8) approximately 10(-7) M) maximally induced the activation of both Raf-1 kinase and mitogen-activated protein (MAP) kinases at 4 and 8 min, respectively, followed by an increase in protein synthesis at 24 h. All of these hypertrophic responses were completely blocked by pretreatment with BQ123, an antagonist selective for the ET-1 type A receptor subtype, but not by BQ788, an ET-1 type B receptor-specific antagonist. BQ123 also suppressed stretch-induced activation of MAP kinases and an increase in phenylalanine uptake by approximately 60 and 50%, respectively, but BQ788 did not. ET-1 was constitutively secreted from cultured cardiomyocytes, and a significant increase in ET-1 concentration was observed in the culture medium of cardiomyocytes after stretching for 10 min. After 24 h, an approximately 3-fold increase in ET-1 concentration was observed in the conditioned medium of stretched cardiomyocytes compared with that of unstretched cardiomyocytes. ET-1 mRNA levels were also increased at 30 min after stretching. Moreover, ET-1 and ATII synergistically activated Raf-1 kinase and MAP kinases in cultured cardiomyocytes. In conclusion, mechanical stretching stimulates secretion and production of ET-1 in cultured cardiomyocytes, and vasoconstrictive peptides such as ATII and ET-1 may play an important role in mechanical stress-induced cardiac hypertrophy.
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PMID:Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. 862 24

Endothelin-1 (ET-1) is a 21-amino acid peptide hormone released from myocardial and endothelial cells, whose receptors (both ETA and ETB are expressed in the myocardium. We report here that ET-1 inhibits the cardiac delayed rectifier K+ current (IK) via a pertussis toxin (PTX)-sensitive mechanism. Ventricular myocytes enzymatically isolated from guinea pig hearts were voltage-clamped by the conventional whole-cell and nystatin-perforated patch technique (intrapipette and extrapipette K+ concentrations, 150 and 5.4 mmol/L, respectively) in the presence of nifedipine (2 mumol/L). Amplitudes of tail and steady state (2-second pulse) currents were measured as IK. ET-1 suppressed the basal IK by 20.9 +/- 2.3% in a concentration-dependent manner, with an IC50 of 1.1 +/- 0.3 nmol/L (n = 19), although it did not suppress the basal IK using the nystatin method. E-4031 (5 mumol/L), a blocker of the rapid component of IK (IKr), did not prevent the inhibitory action of ET-1. ET-1 reduced by 63.4 +/- 6.5% the slow component of IK (IKs) that had been enhanced to approximately 2-fold by isoproterenol (ISO, 20 nmol/L). The action was concentration dependent, with an IC50 of 0.7 +/- 0.4 nmol/L (n = 22), and was also observed using the nystatin method. The effect of ET-1 appeared to be mediated by an ETA receptor, because it was prevented by FR139317, an ETA-selective antagonist (1 mumol/L, n = 4), and sarafotoxin s6c, an ETB-selective agonist (100 nmol/L, n = 4), could not inhibit the ISO-enhanced IK. ET-1 antagonized IKs enhanced by histamine (250 nmol/L, n = 7) and forskolin (500 nmol/L, n = 7) but did not inhibit IKs enhanced by the internal application of cAMP (100 mumol/L, n = 6). Preincubation of myocytes with PTX (5 micrograms/mL for > 60 minutes at 36 degrees C) completely abolished the inhibitory action of ET-1 on the ISO-enhanced IKs (n = 4). Thus, nanomolar ET-1 inhibits IKs via the ETA receptor/PTX-sensitive G protein/PKA pathway.
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PMID:Endothelin-1 inhibits the slow component of cardiac delayed rectifier K+ currents via a pertussis toxin-sensitive mechanism. 924 82

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

PEA-15 (phosphoprotein enriched in astrocytes, Mr = 15,000) is an acidic serine-phosphorylated protein highly expressed in the CNS, where it can play a protective role against cytokine-induced apoptosis. PEA-15 is a major substrate for protein kinase C. Endothelins, which are known to exert pleiotropic effects on astrocytes, were used to analyze further the processes involved in PEA-15 phosphorylation. Endothelin-1 or endothelin-3 (0.1 microM) induced a robust phosphorylation of PEA-15 that was abolished by the removal of extracellular calcium, but only diminished by inhibitors of protein kinase C. Microsequencing of phosphopeptides generated by digestion of PEA-15 following endothelin-1 treatment identified two phosphorylated residues: Ser104, previously recognized as the protein kinase C site, and a novel phosphoserine, Ser116, located in a consensus motif for either protein kinase casein kinase II or calcium/calmodulin-dependent protein kinase II (CaMKII). Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C. Treatment of intact astrocytes with okadaic acid enhanced the phosphorylation of the CaMKII site. These results demonstrate that PEA-15 is phosphorylated in astrocytes by CaMKII (or a related kinase) and by protein kinase C in response to endothelin.
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PMID:Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro. 972 57

The mechanism of Ca2+ sensitization of contraction has not been elucidated in airway smooth muscle (SM). To determine the role of a small G protein, rhoA p21, and its target protein, rho-associated coiled coil-forming protein kinase (ROCK), in receptor-coupled Ca2+ sensitization of airway SM, we studied the effect of (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexane carboxamide dihydrochloride, monohydrate (Y-27632), a ROCK inhibitor, on isometric contractions in rabbit tracheal and human bronchial SM. Y-27632 completely reversed 1 microM carbachol (CCh)-induced contraction of intact trachea with a concentration producing half-maximum inhibition of effect (IC50) of 1.29 +/- 0.2 microM (n = 5). Although 4beta-phorbol 12,13-dibutyrate (1 microM)-induced Ca2+ sensitization was relatively resistant to Y-27632 in alpha-toxin-permeabilized trachea, CCh (100 microM) plus guanosine triphosphate (GTP) (3 microM)- and guanosine 5'-O-(3'-thiotriphosphate) (10 microM)-induced contractions were relaxed completely by Y-27632 with IC50 of 1.44 +/- 0.3 (n = 6) and 1.15 +/- 0.3 microM (n = 6). Endothelin-1 (1 microM) plus GTP (3 microM)- developed force was also reversed by Y-27632 with IC50 of 4. 10 +/- 1.1 microM (n = 6) in the alpha-toxin-permeabilized bronchus. Both the rabbit and human SM expressed rhoA p21, ROCK I, and its isoform ROCK II. Collectively, rho/ROCK-mediated Ca2+ sensitization plays a central role in the sustained phase of airway SM contraction, and selective inhibition of this pathway may become a new strategy to resolve airflow limitation in asthma.
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PMID:Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y-27632 through inhibition of Ca2+ sensitization. 1034 Sep 38

Neonatal pulmonary artery smooth muscle cells (PASMCs) exhibit enhanced growth capacity and increased growth responses to mitogenic stimuli compared with adult PASMCs. Because intracellular signals mediating enhanced growth responses in neonatal PASMCs are incompletely understood, we questioned whether 1) Gq agonists increase cAMP content and 2) increased cAMP is proproliferative. Endothelin-1 and angiotensin II increased both cAMP content and proliferation in neonatal but not in adult PASMCs. Inhibition of protein kinase C and protein kinase A activity nearly eliminated the endothelin-1- and angiotensin II-induced growth of neonatal PASMCs. Moreover, cAMP increased proliferation in neonatal but not in adult cells. Protein kinase C-stimulated adenylyl cyclase was expressed in both cell types, suggesting that insensitivity to stimulation of cAMP in adult cells was not due to decreased enzyme expression. Our data collectively indicate that protein kinase C stimulation of cAMP is a critical signal mediating proliferation of neonatal PASMCs that is absent in adult PASMCs and therefore may contribute to the unique proproliferative phenotype of these neonatal cells.
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PMID:Mechanisms regulating cAMP-mediated growth of bovine neonatal pulmonary artery smooth muscle cells. 1036 26


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