Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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) is a hypertensive peptide, which is expressed in the rat adrenal gland, where it stimulates aldosterone secretion from zona glomerulosa (ZG) by activating the ETb receptor subtype. A higher effectiveness of ET-1 has been frequently observed when the integrity of adrenal tissue is preserved. Hence, we compared the aldosterone secretagogue action of ET-1 on dispersed rat ZG cells and capsule-ZG strips. ET-1 concentration-dependently raised aldosterone output by both preparations with similar potency. However, the efficacy of the maximal effective concentration of ET-1 (10-8 M) was about 2.7-fold higher in capsule-ZG strips. The ETb-receptor antagonist BQ-788 (10-7 M) abolished aldosterone response to 10-8 M ET-1 in both ZG preparations, while the ETa receptor antagonist BQ-123 was ineffective. The aldosterone secretagogue action of 10-8 M ET-1 on dispersed ZG cells was concentration-dependently suppressed by the protein kinase (PK) inhibitor calphostin-C. Conversely, both calphostin-C and the nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) evoked a concentration-dependent partial reversal of the aldosterone response to 10-8 M ET-1 of capsule-ZG strips. The NO donor L-arginine enhanced basal aldosterone yield of capsular strips, but not dispersed ZG cells. The PKA, cyclooxygenase and lipoxygenase inhibitors H-89, indomethacin and phenidone, as well as the beta-adrenoceptor antagonist l-alprenolol, were ineffective. Collectively, these findings allow us to conclude that in the rat i) the ETb receptor-mediated PKC activation is the main signaling mechanism involved in the direct stimulatory effect of ET-1 on ZG cells; and ii) the higher responsiveness of capsular strips to ET-1 may be accounted for by the ETb receptor-mediated release by stromal elements of NO, which in turn increases aldosterone secretion from ZG cells in a paracrine manner.
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PMID:Comparison of the signaling mechanisms involved in the ETB receptor-mediated secretagogue action of endothelin-1 on dispersed zona glomerulosa cells and capsule-zona glomerulosa preparations of the rat adrenal gland. 1060 72

We investigated the mechanism of Endothelin-1 regulation by transforming growth factor-beta1 (TGF-beta1) in bovine pulmonary artery endothelial cells (BPAECs) and in isolated perfused rat lungs. Our data show that TGF-beta1 induces ET-1 gene expression and ET-1 peptide synthesis in BPAECs. The induction of preproET-1 mRNA level was due to de novo transcription, as well as mRNA stabilization, and new protein synthesis was not required for this induction. To investigate the role of cAMP-protein kinase A pathway in TGF-beta1-stimulated-ET-1 induction, we exposed BPAECs to various compounds which modulate this pathway. Dibutyryl-cAMP led to an increase in preproET-1 mRNA and Rp-cAMP abolished the induction of preproET-1 mRNA and ET-1 peptide by TGF-beta1. TGF-beta1 increased cAMP in BPAECs. Dexamethasone up-regulated preproET-1 mRNA expression and ET-1 peptide synthesis under basal and TGF-beta1-stimulated conditions. In isolated perfused rat lungs, TGF-beta1 increased preproET-1 mRNA abundance whereas Rp-cAMP inhibited the TGF-beta1-induced ET-1 gene activation. Thus our data suggest that TGF-beta1 stimulates ET-1 gene expression in BPAECs and in rat lungs via a cAMP dependent mechanism.
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PMID:Transforming growth factor-beta1 induces endothelin-1 in a bovine pulmonary artery endothelial cell line and rat lungs via cAMP. 1106 80

Endothelin-1 (ET-1) is a 21 amino acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have found that ET-1 stimulates glucose uptake in 3T3-LI adipocytes. In this report, we extend the studies to neonatal rat cardiomyocytes. ET-1, but not angiotensin-II (A-II), stimulated glucose uptake in a dose-dependent manner with an EC50 value at approximately 1 nM, and an approximately 2-fold stimulation at 100 nM. As a comparison, insulin stimulated glucose uptake in a dose-dependent manner with an EC50 value at 1 nM, and a 2.5-fold stimulation at 100 nM. Western blot analysis shows that ET-1 stimulated the translocation of insulin-responsive aminopeptidase (IRAP), an aminopeptidase in GLUT4 (glucose transporter)-containing vesicles, from the cytoplasm to the plasma membrane. The effect of ET-1 on glucose uptake was blocked by A-127722, an antagonist selective for the ET(A)-receptor. ET-1 treatment did not induce phosphorylation of insulin receptor-beta (IRbeta), insulin receptor substrate-1 (IRS-1) or Akt, but stimulated the phosphorylation of extracellular signal-regulated kinase (ERK1/2). The effect of ET-1 on glucose uptake was not inhibited by inhibitors for protein kinase C (PKC), protein kinase A (PKA) and phosphatidylinositol-3-kinase (PI3'-kinase). Our results show that ET-1 stimulates glucose uptake in neonatal rat cardiomyocytes via activation of the ET(A)-receptor.
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PMID:Endothelin stimulates glucose uptake via activation of endothelin-A receptor in neonatal rat cardiomyocytes. 1107 71

Endothelin-1 (ET-1)[1-31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1-21]. However, at variance with ET-1[1-21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1-31] did not elicit such effect. Both ET-1[1-21] and ET-1[1-31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10(-8) M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1-21] displaced both [(125)I]PD-151242 binding to ETA receptors and [(125)I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1-31] displaced only [(125)I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1-31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1-31] (10(-8) M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1-31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1-31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade.
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PMID:Endothelin-1[1-31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells. 1115 May 8

Endothelin-1 (Et-1) is a peptide synthesized by endothelial cells (ECs) both in culture and in vivo. Cyclic strain induces gene expression of Et-1, however, the molecular mechanisms remain unclear. Since cyclic strain induces a sustained increase in intracellular reactive oxygen species (ROS), we hypothesized that the ROS could be a modulator in strain-induced Et-1 gene expression. Human umbilical vein ECs (HUVECs) subjected to cyclic strain had increased Et-1 secretion. Pretreatment of HUVECs with antioxidants, catalase (300 U/ml) or 1,3-dimethyl-2-thiourea (DMTU, 0.1 mm), abolished the strain-induced Et-1 release. ECs strained for 6 h had elevated Et-1 mRNA levels. In contrast, ECs treated with catalase or DMTU did not have increase Et-1 mRNA levels stimulated by cyclic strain. Bovine aortic ECs (BAECs) transfected with fusion plasmid containing Et-1 5'-flanking sequence (4.4 kb) and chloramphenicol acetyltransferase reporter gene produced a maximal Et-1 promoter activity after undergoing strain for 6 h, whereas pretreatment with catalase decreased this activity. BAECs cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or catalytically inactive mutant of extracellular signal-regulated kinase (mERK2) had inhibited strain-induced Et-1 promoter activity, indicating the Ras/Raf/ERK pathway was involved; moreover, ERK phosphorylation was induced in ECs which were strained. This strain-activated ERK phosphorylation was attenuated in the presence of catalase. Functional analysis of the Et-1 promoter with site-directed mutagenesis indicates that the activator protein-1 (AP-1) binding site had to be within 143 base-pairs upstream of transcription initiation site for strain-induced promoter activity. Pretreatment of ECs with catalase also decreased the strain-induced promoter activity in the minimal construct (-143 bp). Our data demonstrate that strain-induced Et-1 gene expression is modulated by ROS via Ras/Raf/ERK signaling pathway, and indicate the responsiveness of the AP-1 binding site for strain-induced Et-1 expression.
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PMID:Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. 1160 23

In normal human melanocytes various mitogens activate the mitogen-activated protein kinases ERK1/2 and the downstream transcription factor CREB (Ca2+/cAMP response element binding protein). Endothelin-1, basic fibroblast growth factor, and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation. The former two mitogens phosphorylated ERK1/2, its substrate p90rsk, and CREB. Alpha-melanotropin, forskolin, or dibutyryl cAMP failed to phosphorylate any of those targets, however. The concomitant presence of endothelin-1, basic fibroblast growth factor, and alpha-melanotropin significantly potentiated CREB phosphorylation. The mitogen-induced phosphorylation of p90rsk and CREB was dependent on ERK1/2 activation, and was mediated by intracellular calcium mobilization and by protein kinase C and tyrosine kinase activation, but not by activation of the cAMP-dependent protein kinase A. Exposure of melanocytes to ultraviolet radiation B resulted in the phosphorylation of the stress-induced mitogen- activated protein kinases p38 and JNK/SAPK, but not ERK1/2. Ultraviolet radiation B induced the phosphorylation of CREB via a pathway that was partially dependent on p38, but had no effect on p90rsk or ERK1/2. Therefore, in human melanocytes, CREB is a common downstream target for distinct effectors that are involved in either mitogenic signaling or stress signaling initiated by ultraviolet radiation B.
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PMID:Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. 1184 50

1. Endothelin-1 (ET-1) stimulates integrin-dependent adhesion of neutrophil granulocytes to endothelial cells, one of the early key events in acute inflammation. However, the signalling pathway(s) of ET-1-stimulated neutrophil adhesive responses has not been elucidated. Previous studies indicated that extracellular signal-regulated kinase (ERK) activation could mediate rapid responses of neutrophil granulocytes to various stimuli. In this study, we investigated the role of ERK signalling in human neutrophil granulocytes challenged with ET-1. 2. ET-1 rapidly down-regulated the expression of L-selectin and up-regulated the expression of CD11b/CD18 on the neutrophil surface. Concomitantly, ET-1 induced homotypic adhesion (aggregation) of neutrophils, that was blocked by a monoclonal antibody to CD18. 3. ET-1, through ET(A) receptors, evoked activation of Ras and subsequent phosphorylation of Raf-1, mitogen-activated protein kinase kinase (MAPK/ERK kinase) and ERK 1/2. ERK activation by ET-1 was rapid, concordant with the kinetics of ET-1-stimulated neutrophil aggregation. 4. Neutrophil responses to ET-1 were markedly attenuated by the MAPK/ERK kinase inhibitor PD98059, whereas inhibitors of p38 MAPK, tyrosine kinases and phosphatidylinositol 3-kinase had no detectable effects. We have observed a tight correlation between neutrophil ERK activation and homotypic adhesion. 5. These data indicate an essential role for ERK in mediating ET-1-stimulated adhesive responses of human neutrophil granulocytes.
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PMID:Extracellular signal-regulated kinase plays an essential role in endothelin-1-induced homotypic adhesion of human neutrophil granulocytes. 1187 23

Endothelin-1 (ET1) and ATP stimulate contraction and hypertrophy of vascular smooth muscle cells (VSMC) by activating diverse signalling pathways. In this study, we show that in VSMC, ET1 and ATP stimulate transient and sustained activation of protein kinase A (PKA), respectively. Using a dominant negative PKA mutant (PKA-DN), we examined the functional significance of PKA activation in the signalling of ET1 and ATP. Overexpression of PKA-DN did not alter the ET1- or ATP-induced phosphorylation of the extracellular signal-regulated protein kinase, Erk2. ATP stimulated a profound, PKA-dependent activation of cAMP-response element (CRE), whereas the effect of ET1 was negligible. Both ET1 and ATP stimulated serum response factor (SRF)-dependent gene expression. Overexpression of PKA-DN potentiated the effects of ET1 and ATP on SRF activity, whereas stimulation of PKA by isoproterenol, forskolin or by overexpression of the PKA catalytic subunit decreased SRF activity. These data demonstrate that (i) PKA negatively regulates SRF activity and (ii) ET1 and ATP stimulate opposing pathways, whose balance determines the net activity of SRF.
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PMID:Functional significance of protein kinase A activation by endothelin-1 and ATP: negative regulation of SRF-dependent gene expression by PKA. 1268 47

C-type natriuretic peptide (CNP) and endothelin-1 are paracrine peptides with opposing effects on cardiac myocyte contraction and intracellular cGMP production. Elevated levels of both endothelin-1 and CNP are found in patients with congestive heart failure. These factors may be related to positive and negative regulation of cell apoptosis in the failing heart. To evaluate the effect of CNP and endothelin-1 on apoptosis of cardiac myocytes and the possible mechanisms involved, primary cardiac myocytes were prepared from neonatal Sabra rats. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Annexin V in situ staining. The TUNEL method was used to measure the apoptotic index. CNP and the cGMP derivative, 8-br-cGMP, induced apoptosis of cardiac myocytes. CNP-induced apoptosis could be blocked by HS 142-1 (a mixture of 20-30 kinds of linear beta-1, 6-glucan esterified by capronic acid, an antagonist of type A and B natriuretic peptide receptors), and KT 5823 (C29H25N3O5), the inhibitor of cGMP-dependent protein kinase). Alpha-difluoromethylornithine (DFMO), the irreversible inhibitor of ornithine decarboxylase, also induced apoptosis to a similar extent. CNP and 8-br-cGMP caused a marked reduction of intracellular ornithine decarboxylase expression, as determined by Western blot analysis and immunohistochemical assay. Preincubation with endothelin-1 attenuated CNP- and 8-br-cGMP-induced cardiomyocyte apoptosis. Endothelin-1 also antagonized the CNP- and 8-br-cGMP-induced reduction of intracellular ornithine decarboxylase expression. These results suggest that CNP has a proapoptotic effect on neonatal rat cardiac myocytes. The effect is mediated via natriuretic peptide receptors and is due to an elevation of intracellular cGMP, which reduces the expression of intracellular ornithine decarboxylase and probably the production of polyamines. Endothelin-1 protects cardiac myocytes against CNP-induced apoptosis by influencing the cGMP-dependent pathway, and this effect is probably mediated through both a reduction of cGMP and antagonism of the CNP-induced reduction of intracellular ornithine decarboxylase expression.
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PMID:The opposing effects of endothelin-1 and C-type natriuretic peptide on apoptosis of neonatal rat cardiac myocytes. 1290 91

Endothelin-1 (ET-1) affects glucose uptake in adipocytes and may play an important role in adipose physiology. One of the principal functions of adipose tissue is the provision of energy substrate through lipolysis. In the present study, we investigated the effects of ET-1 on lipolysis in 3T3-L1 adipocytes. When glycerol release in the culture medium was measured as an index of lipolysis, the results showed that ET-1 caused a significant increase that was time and dose dependent. With a concentration of 10 nM ET-1, stimulation of glycerol release plateaued after 4 h of exposure. This effect was inhibited by the ETA receptor antagonist BQ-610 (10 microM) but not by the ETB receptor antagonist BQ-788 (10 microM). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the cAMP-dependent protein kinase A-mediated, phospholipase A2 (PLA2)-mediated, protein kinase C (PKC)-mediated, phosphatidylinositol 3 (PI 3)-kinase-mediated, and the mitogen-activated protein kinase (MAPK)-mediated pathways. Inhibition of adenylyl cyclase activation by SQ-22536 (100 microM) did not block ET-1-induced lipolysis. Pretreatment of adipocytes with the PLA2 inhibitor dexamethasone (100 nM), the PKC inhibitor H-7 (6 microM), or the PI 3-kinase inhibitor wortmannin (100 nM) also had no effect. ET-1-induced lipolysis was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation using PD-98059 (75 microM), whereas a p38 MAPK inhibitor (SB-203580; 20 microM) had no effect. Results of Western blot further demonstrated that ET-1 induced ERK phosphorylation. These data show that ET-1 induces lipolysis in 3T3-L1 adipocytes via a pathway that is different from the conventional cAMP-dependent pathway used by isoproterenol and that involves ERK activation.
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PMID:Endothelin-1 induces lipolysis in 3T3-L1 adipocytes. 1567 Oct 81


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