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)

We investigated the regulatory mechanisms of endothelin (ET)-1 production in cultured rat mesangial cells (MC), with a special focus on the roles of protein kinase A (PKA)- and protein kinase C (PKC)-mediated signaling systems. Vasoactive agents and growth promoting factors, including platelet-derived growth factor, vasopressin and thrombin, which act through receptors coupled to the phospholipase C-mediated signaling system, as well as phorbol ester and fetal calf serum stimulated ET-1 production. This effect was attenuated in PKC-depleted or H-7 (a PKC inhibitor) treated MC. On the other hand, an increase in intracellular cyclic AMP by forskolin or beta-adrenergic agonist, isoproterenol, which act as anti-mitogenic agents, inhibited serum-stimulated ET-1 production. In addition this effect was mimicked by the addition of 8-bromo-cyclic AMP to the medium. The effect of isoproterenol was abolished by propranolol. H-8, a PKA inhibitor, attenuated the inhibitory effect of forskolin. These findings suggest that ET-1 production in MC is regulated by interaction of both positive and negative signals mediated by PKC- and PKA-dependent mechanisms.
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PMID:Regulation of endothelin-1 production in cultured rat mesangial cells. 131 23

Endothelin (ET) and GnRH act through specific receptors to promote Ca2+ mobilization and influx pathways in pituitary gonadotrophs. In the present study cytoplasmic calcium ([Ca2+]i) and secretory responses to these two agonists are compared. In single gonadotrophs, low concentrations of both agonists cause oscillatory [Ca2+]i responses after a latent period. Such responses usually consist of discrete transients arising from the normal resting level, but are sometimes super-imposed on an elevated basal calcium level. At high doses, ET-1 and GnRH induce biphasic responses, composed of a spike phase followed by a plateau that often shows high frequency and low amplitude Ca2+ transients. The duration of the latent period and the frequency of the subsequent oscillations are correlated, and both are dependent on agonist concentration. The frequencies and amplitudes of Ca2+ spiking are also interrelated; increases in frequency are followed by more rapid decreases in the amplitude of the Ca2+ transients. After K(+)-induced depolarization, gonadotrophs retain their oscillatory Ca2+ responses to ET-1 and GnRH, with the same frequency as controls. Activation of protein kinase-C by phorbol esters does not alter the frequency of ET-induced Ca2+ transients, but significantly reduces their amplitudes. In contrast, treatment with nanomolar concentrations of thapsigargin converts ET-induced oscillations into a biphasic response, suggesting that Ca(2+)-ATPase in the endoplasmic reticulum participates in the oscillatory mechanism. The two agonists differ in their threshold doses and concentration dependence, ET being significantly less potent than GnRH. Also, gonadotrophs stimulated by ET-1 exhibit different post-treatment responsiveness than those exposed to GnRH. While GnRH-treated cells recover their full [Ca2+]i and secretory responses within 30 min as well as normal [Ca2+]i and secretory responses to ET-1, endothelin-treated cells are refractory to further stimulation with ET and exhibit either attenuated or enhanced Ca2+ and LH responses to GnRH, depending on the duration of exposure to ET-1 and the subsequent recovery period. These data indicate that both receptors use the same mechanism(s) for Ca2+ release, but have different capacities to generate, maintain, and reinitiate the Ca2+ signal.
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PMID:Differential actions of endothelin and gonadotropin-releasing hormone in pituitary gonadotrophs. 144 20

Direct pituitary effects of vasoactive intestinal contractor (VIC), which has been described recently to be the rat form of endothelin-2 (ET-2), were compared to those previously reported for rat ET-1, rat ET-3, and human ET-2. In static incubations of cultured dispersed anterior pituitary cells, the minimum effective dose of VIC necessary to inhibit PRL release after 1-h incubation was 1 pM, and the maximum effective dose was 1 nM. Similar inhibition was observed with human ET-2. The minimum effective inhibitory dose of ET-1 was also 1 pM; however, that of ET-3 was 0.1 nM. PRL release inhibition by VIC was not mediated via the D2-dopamine receptor and was not prevented by calcium channel blockade with 100 nM nifedipine. The inhibitory effect of VIC was not present in cells treated with 100 nM staurosporine, a dose that inhibits protein kinase-C activity. Time-course studies revealed a transient stimulation of PRL release with higher doses of VIC (10 and 100 nM), which occurred within the first 15 min of incubation and was unaffected by calcium channel blockade or inhibition of protein kinase-C activity. No stimulation of PRL release was observed with doses of VIC lower than 10 nM. Instead, we observed the maintenance of the inhibitory effect for 4 h of incubation. GH release was not significantly affected by doses of VIC ranging from 10(-13)-10(-7) M; however, the release of LH was slightly, yet significantly, stimulated by 10 and 100 nM VIC. This release was prevented by pretreatment with nifedipine, but unaffected by protein kinase-C inactivation. A physiological role for VIC (rat ET-2) in the control of lactotroph function is suggested by its effectiveness at picomolar doses and its long-lasting action.
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PMID:Comparison of the pituitary effects of the mammalian endothelins: vasoactive intestinal contractor (endothelin-beta, rat endothelin-2) is a potent inhibitor of prolactin secretion. 153 64

Endothelin (ET-1) is a 21-amino acid peptide with potent vasopressor and vasoconstrictive properties. Specific, high affinity receptors for ET-1 have been found in the adrenal gland. The stimulation by ET-1 of aldosterone secretion in cultured calf zona glomerulosa cells was shown to depend on the serum used for culturing and was not related to the growth-promoting effects of serum or the response to another secretagogue, such as angiotensin-II. In this study, binding of [125I]ET-1 to crude membrane preparations from calf adrenal cortex slices showed that ET-1 binding was greater in the outer slices, corresponding to the zona glomerulosa, than in inner slices, corresponding to the zona fasciculata. ET-1 stimulated aldosterone, but not cortisol, biosynthesis. Adrenal zona glomerulosa preincubated with ET-1 resulted in homologous down-regulation. Since ET-1 action involves activation of protein kinase-C (PKC), we studied the effect of a phorbol ester (PMA) on the down-regulation of ET-1 receptors. PMA decreased the number of cell surface receptors, and its effect was prevented by pretreatment with the PKC inhibitors H-7 and sphyngosine. Agonist-mediated down-regulation could not be blocked by pretreatment with PKC inhibitors, suggesting that PKC is involved in phorbol ester-mediated, but not agonist-mediated down-regulation of ET-1 receptors. Both effectors increased the endocytosis rate constant as well as the steady state cytosolic membrane-bound ratio for ET-1 receptors, suggesting that the decrease in the number of cell surface receptors is at least partially due to an increased internalization of the hormone-receptor complex. ET-1 and PMA decreased the incorporation of [3H]thymidine into calf zona glomerulosa cell cultures. We conclude that ET-1 and PMA have similar effects on glomerulosa cells, producing down-regulation of ET-1 receptors and an antimitogenic effect, but these actions are through different mechanisms.
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PMID:Effects of endothelin-1 on its receptor concentration and thymidine incorporation in calf adrenal zona glomerulosa cells: a comparative study with phorbol esters. 216 11

Vascular endothelial cells (ECs) are constantly subjected to mechanical strain due to relaxation and contraction of vessel walls. The effects of cyclical strain on endothelin-1 (Et-1) secretion and Et-1 mRNA levels in human umbilical vein ECs were examined. Cultured ECs grown on a flexible membrane base were deformed by negative pressure (16 kPa at 60 cycles/min). Cells subjected to strain showed increased Et-1 secretion (0.54 ng/hr/10(6) cells) compared with unstrained control cells (0.22 ng/hr/10(6) cells). Northern blot analysis of cells strained for 2 hours or longer demonstrated a sustained elevated Et-1 mRNA level at more than double the level in unstrained controls. This strain-induced ET-1 mRNA level returned to its basal level 2 hours after the release of strain. Cells treated with actinomycin D before or during strain treatment showed no strain-induced gene expression. Pretreatment of ECs with a protein kinase C (PKC) inhibitor, Calphostin C, strongly inhibited the strain-induced Et-1 gene expression. Pretreatment of ECs with cAMP- or cGMP-dependent protein kinase inhibitors (KT5720 or KT5823) only partially inhibited the increased Et-1 mRNA levels in strain-treated cells. EGTA strongly inhibited the Et-1 gene expression. The intracellular calcium chelator BAPTA/AM also showed an inhibitory effect on Et-1 mRNA levels. We conclude that mechanical strain can stimulate the secretion of Et-1 from ECs by increasing Et-1 mRNA levels via transcription, and that this gene induction is mediated predominantly via the PKC pathway and requires extracellular Ca2+. This strain-induced Et-1 gene expression in ECs may contribute to the regulation of vascular tone and structure in normal and pathological states of the cardiovascular system.
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PMID:Mechanical strain increases endothelin-1 gene expression via protein kinase C pathway in human endothelial cells. 753 82

To investigate the nuclear signalling pathway induced by endothelin (ET) isopeptides, we have established permanent Chinese hamster ovary (CHO) cell lines, CHO-ETA/fos-lacZ and CHO-ETB/fos-lacZ, that produce both a c-fos-beta-galactosidase fusion protein and either the type A or the type B human ET receptor. These cell lines permitted a colorimetric measurement of c-fos expression, which was induced by the signal transduction system with ET receptors and ET isopeptides. We found that the ET-1-dependent c-fos expression was so efficient that it could respond to low concentrations (even a physiological concentration) of ET-1. For example, CHO-ETA/fos-lacZ and CHO-ETB/fos-lacZ responded to ET concentrations of 5 x 10(-9) M and 5 x 10(-13) M respectively. Using this highly sensitive system, the H-7 sensitive protein kinase was found to be involved in signal transduction mediated by ETA, and also partly in the ETB-mediated pathway. These lines of evidence suggest that c-fos expression occurs through at least two different pathways, depending on the concentration of ET in plasma.
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PMID:Differential regulation of c-fos gene expression by two types of human endothelin receptor in Chinese hamster ovary cells. 806 Apr 82

Endothelin (ET), a powerful vasoconstrictive peptide, is distributed ubiquitously in various organs, including the vascular endothelium and tubules of the kidney. Although localized more abundantly to the glomerulus and inner medullary collecting duct, ET receptors have been identified in the proximal tubule. The possible effects of ET on proximal tubule transport and the potential role of second messengers in this process have not been described fully. To define the role of ET in proximal tubule transport, renal cortical slices were incubated for 3 min in the presence of various concentrations of ET. Incubation with low concentrations of ET-1 (1 x 10(-9) to 1 x 10(-11) M) within the physiological range stimulated both Na(+)-Pi cotransport and Na+/H+ exchange. Pretreatment with staurosporine (0.6 microM) for 25 min abolished completely the ET-induced effects on Na(+)-Pi cotransport and Na+/H+ exchange. Similarly, preincubation with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (200 nM) also abolished the effects of ET on these transporters. Incubation with ET decreased significantly intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Intravenous administration of pertussis toxin for 2 days prevented the ET-induced decrease in cAMP and abolished the stimulatory effects of ET on Na(+)-Pi cotransport and Na+/H+ exchange. These findings provide indirect evidence that ET participates in the regulation of proximal tubular Pi and bicarbonate homeostasis. These effects of ET are mediated by activation of protein kinase C and cAMP-dependent protein kinase A.
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PMID:Effects of endothelin on rat renal proximal tubule Na(+)-Pi cotransport and Na+/H+ exchange. 818

Endothelins (ET-1, -2, -3) display pleiotropic activities, by signalling through G-protein-coupled membrane receptors. We show here that ET-1 and ET-3 stimulate within minutes the tyrosine phosphorylation of a 42 kDa protein (p42) in primary cultures of mouse embryo astrocytes, but not in any of two subclones of rat astrocytoma C6 cells. This effect, measured by anti-phosphotyrosine immunoblotting of cell extracts, was also observed in response to bradykinin, platelet-derived growth factor, the phorbol ester phorbol 12-myristate 13-acetate and the G-protein activator fluoroaluminate. Pretreatment of cells with pertussis toxin, which inactivates Gi/G(o) proteins, did not affect these responses. However, down-regulation of protein kinase C completely blocked the response to phorbol ester and fluoroaluminate and at least partially impaired the ET-1-stimulated phosphorylation of p42. We have identified p42 as p42mapk, a mitogen-activated protein (MAP) kinase, on the basis of the following data: by sequential immunoblotting with antiphosphotyrosine and anti-MAP kinase antibodies, (i) similar kinetics are observed for p42 phosphorylation and the decrease in p42mapk electrophoretic mobility, likely corresponding to its tyrosine/threonine phosphorylation [de Vries-Smits, Boudewijn, Burgering, Leevers, Marshall and Bos (1992) Nature (London) 357, 602-604]; (ii) p42 and the shifted form of p42mapk co-migrate on SDS/PAGE; (iii) the myelin-basic-protein kinase activity of p42mapk is stimulated by ET-1, in parallel with the tyrosine phosphorylation of p42. In conclusion, these findings strongly suggest that endothelins can stimulate the tyrosine phosphorylation and activation of p42mapk in astrocytes, via pertussis-toxin-insensitive G protein and protein kinase C-dependent and -independent pathways.
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PMID:Endothelins stimulate tyrosine phosphorylation and activity of p42/mitogen-activated protein kinase in astrocytes. 834 18

Astrocytes have been shown to express endothelin (ET) receptors functionally coupled, via different heterotrimeric G proteins, to several intracellular pathways. To assess the relative contribution of each subtype in the astrocytic responses to ET-1, effects of BQ123, an antagonist selective for the ET receptor subtype A (ETA-R), and IRL1620, an agonist selective for the ET receptor subtype B (ETB-R), were investigated in primary cultures of rat astrocytes. Binding experiments indicated that the ETB-R is the predominant subtype in these cells. Inhibition of forskolin-stimulated cyclic AMP production was observed under. ETB-R stimulation. Bordetella pertussis toxin (PTX) pretreatment completely abolished this effect, indicating that this pathway is coupled to the ETB-R via Gi protein. Increases of tyrosine phosphorylation of cellular proteins, stimulation of mitogen-activated protein kinase (MAPK), and DNA synthesis were also found to be mediated by the ETB-R, but through PTX-insensitive G protein. IRL1620-induced MAPK activation involved the adapter proteins Shc and Grb2 and the serine/threonine kinase Raf-1. This study reveals that the various effects of ET-1 in astrocytes are mediated by the ETB-R, which couples to multiple signaling pathways including the MAPK cascade.
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PMID:Coupling of ETB endothelin receptor to mitogen-activated protein kinase stimulation and DNA synthesis in primary cultures of rat astrocytes. 859 14

Two important mediators of endothelium-dependent regulation of vascular smooth muscle tone and proliferation are nitric oxide (NO) and endothelin (ET-1). An imbalance between NO and ET-1 may contribute to the alterations in vascular tone characteristic of cardiovascular disease. The objective of this study was to determine whether NO regulates ET receptors in cultured rat superior mesenteric artery vascular smooth muscle cells (RVSMC). Chronic treatment of quiescent RVSMC with any one of three chemically dissimilar NO-generating drugs, S-nitroso-N-acetyl penicillamine (SNAP), sodium nitroprusside (SNP), and isosorbide dinitrate (ISDN) produced a significant dose- and time-dependent increase in the number of ET-A receptors, while concomitantly increasing the affinity of ET-1 for this receptor. This effect was mimicked by both 8-bromo-cGMP and 8-bromo-cAMP. The requirement of both protein and RNA synthesis and activation of a cAMP-dependent protein kinase (A-kinase) was demonstrated following inhibition of this regulation by cycloheximide, actinomycin D and KT5720 (a specific A-kinase inhibitor), respectively. In addition, the cytokine interleukin 1 beta (IL-1 beta) which induced NOS activity with subsequent NO synthesis in vascular smooth muscle, also caused a similar upregulation of ET receptors. This effect was attenuated in the presence of the specific NOS inhibitor, L-NAME. To assess the possible functional consequences of this NO-mediated upregulation, the effect of SNAP pretreatment on isolated vessel reactivity was determined. In both superior mesenteric artery and thoracic aorta rings, SNAP pretreatment caused a significant increase in the maximal force of contraction to ET-1. Collectively, these data suggest that NO regulates ET-A receptors in vitro through a cGMP-dependent mechanism via activation of the cAMP-dependent protein kinase. We conclude that a similar interaction between NO and ET-1 may be operational in vivo.
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PMID:Regulation of endothelin receptors by nitric oxide in cultured rat vascular smooth muscle cells. 860 Jan 50


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