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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify a possible involvement of the vasoconstrictive peptide endothelin in the regulation of endothelial cell-mediated fibrinolytic system, confluent cultures of vascular endothelial cells from human umbilical vein were incubated in serum-free medium in the presence of endothelin-1 at 100 nM and below, and tissue plasminogen activator antigen (t-PA:Ag) in the medium was determined by enzyme immunoassay. Endothelin-1 at 1 nM and above significantly decreased the release of t-PA:Ag from the endothelial cells after a 24 h incubation. The t-PA:Ag release was also decreased by either endothelin-2 or endothelin-3 at 10 nM. The activity of lactate dehydrogenase in the medium was not changed by endothelin-1 at 100 nM and below, suggesting that the peptide did not cause nonspecific cell damage. The decrease in the t-PA:Ag release induced by endothelin-1 occurred in the presence or absence of 8-bromo cyclic AMP, which is an active congener of cyclic AMP; 3-isobutyl-1-methylxanthine, which is an inhibitor of phosphodiesterase; and forskolin, which is a stimulator of adenylate cyclase. These results strongly indicated that cyclic AMP which is known to down-regulate t-PA:Ag release was not involved in the endothelin-1 effect. However, endothelin-1 failed to decrease the t-PA:Ag release in the presence of either calcium ionophore A23187 or EGTA; the ionophore itself markedly decreased the release. The cytosolic calcium accumulation was significantly increased by endothelin-1. These results suggest that endothelin-1 decreases the release of t-PA:Ag from human endothelial cells through an excess accumulation of intracellular, especially cytosolic which would be mediated by an extracellular, calcium-dependent mechanism.
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PMID:Endothelin modulation of tissue plasminogen activator release from human vascular endothelial cells in culture. 137 54

C-type natriuretic peptide and sodium nitroprusside, a nitric oxide donor molecule, induced large increases in cyclic GMP formation in cultured rat brain capillary endothelial cells. Isoproterenol, a potent agonist of adenylate cyclase, potentiated the actions of C-type natriuretic peptide and of sodium nitroprusside. These actions were not observed in the presence of isobutylmethylxanthine and were mimicked by forskolin. Endothelin-1 had no action on basal cyclic GMP levels. It reduced cyclic GMP formation induced by C-type natriuretic peptide and sodium nitroprusside by about 50%. These actions involved an ETA receptor subtype and a Ca(2+)-dependent and protein kinase C-independent mechanism. Finally, increasing cyclic GMP slightly prolonged intracellular Ca2+ transients induced by endothelin-1. The results suggest the presence of extensive cross talk among cyclic AMP, cyclic GMP, and Ca(2+)-dependent mechanisms in endothelial cells of brain microvessels. The relevance of the results to the regulation of the blood-brain barrier permeability is discussed.
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PMID:Cross talk among cyclic AMP, cyclic GMP, and Ca(2+)-dependent intracellular signalling mechanisms in brain capillary endothelial cells. 751 50

Endothelin-1 (ET-1) caused slow-developing and stable vasoconstrictions in isolated rings of rat thoracic aortae with a pD2 value of 7.55 +/- 0.10 compared to pD2 values of 9.30 +/- 0.10 and 8.36 +/- 0.30 for angiotensin II and norepinephrine, respectively. Although the potency of ET-1 was somewhat lower than those of norepinephrine and angiotensin II, the maximal tension generated by ET-1 was comparable to that of norepinephrine and considerably greater than that of angiotensin II. Incubation of aortic rings in the absence of extracellular Ca2+ or in the presence of the Ca2+ channel blocker nifedipine (100 nmol.L-1) greatly attenuated ET-1-induced vasoconstriction. ET-1 (20 nmol.L-1, approximately the ED50 for vasoconstrictions) also caused elevation of cAMP levels in aortic rings after 15 and 25 min of exposure. The cAMP phosphodiesterase inhibitor imidazolidione (Imi, Ro 20-1724, 100 mumol.L-1) potentiated the cAMP responses to ET-1. Rings incubated for 25 min with ET-1 (20 nmol.L-1) showed much larger cAMP elevations caused by colforsin (Col, forskolin 1 mumol.L-1), a direct adenylate cyclase activator and potentiator, than with Col or ET-1 alone. Therefore, ET-1 may utilize at least 2 signal transduction mechanisms, one involving the opening of nifedipine-sensitive Ca2+ channels and the other involving the elevation of cAMP levels, to produce the unusually slow-developing and stable vasoconstrictions in rat aortae.
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PMID:Colforsin or imidazolidione potentiates cAMP elevation caused by endothelin-1 in rat aorta. 780 66

Endothelin-1 (ET-1) is a 21-amino-acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have shown that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes and neonatal rat cardiomyocytes, but the mechanism is not completely understood. ET-1 is known to modulate intracellular Ca(2+) and cAMP levels. Depletion of intracellular Ca(2+) by treating 3T3-L1 adipocytes with EDTA and 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxymethyl ester (MAPTAM) did not have a significant effect on ET-1-induced glucose uptake. Forskolin, a potent stimulator which stimulates adenylate cyclase and increases the intracellular cAMP level, partially inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, but had no significant impact on the effect of ET-1. Forskolin also did not show an effect on the tyrosine phosphorylation of a 75 kDa protein induced by ET-1. Glucosamine treatment causes insulin resistance in cells, possibly by entering the hexosamine biosynthetic pathway. In neonatal rat cardiomyocytes, glucosamine treatment blocked both insulin and ET-1-stimulated glucose uptake and also eliminated the translocation of IRAP, an aminopeptidase in GLUT4-containing vesicles, from the cytoplasm to the plasma membrane. These results suggest that ET-1-induced glucose uptake is independent of its effects on modulating intracellular Ca(2+) and cAMP levels, but is likely linked to the hexosamine biosynthetic pathway.
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PMID:Endothelin-stimulated glucose uptake: effects of intracellular Ca(2+), cAMP and glucosamine. 1219 36

The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes (NHM) by specific paracrine and endocrine factors, and by ultraviolet radiation (UVR). Treatment of NHM with alpha-melanotropin [alpha-melanocyte stimulating hormone (alpha-MSH)] increased MC1R mRNA level; the response was often more pronounced in NHM with a low (NHM-c) than in NHM with a high melanin content (NHM-b). Endothelin-1 increased MC1R mRNA level in NHM regardless of their melanin content. Basic fibroblast growth factor consistently up regulated MC1R mRNA level in NHM-b but not in NHM-c. Activation of protein kinase C by 12-0-tetradecanoylphorbol-13-acetate slightly increased, while stimulation of adenylate cyclase by forskolin markedly up-regulated the MC1R mRNA level. beta-Estradiol increased, and combined treatment with beta-estradiol and alpha-MSH further elevated, MC1R mRNA level in NHM-c and NHM-b. Testosterone reduced, while progesterone had no effect on, MC1R mRNA level. Agouti signaling protein reduced, and UVR down regulated dose-dependently MC1R mRNA level in NHM-b and NHM-c. This effect was reversed 24 h after irradiation with the lower doses of 7 or 14 mJ/cm2, but not after exposure to a higher, more cytotoxic dose of UVR. We conclude that the MC1R is regulated by paracrine factors, including its own ligands, by specific endocrine sex hormones, and by UVR. Differences in the responses of NHM to some of these factors suggest differential regulation of MC1R gene expression, which may contribute to the variation in constitutive and UV-induced cutaneous pigmentation in humans.
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PMID:Regulation of the human melanocortin 1 receptor expression in epidermal melanocytes by paracrine and endocrine factors and by ultraviolet radiation. 1245 85

Endothelin-1 reduces the chronotropic and inotropic effects of the beta-adrenoceptor agonist isoproterenol in rabbit isolated atria. Vascular interactions between endothelin-1 and isoproterenol have not been reported. Rings of the rabbit aorta without endothelium were mounted on myographs to measure isometric tension. Vessels were precontracted to similar levels with phenylephrine (30 micromol/L) or endothelin-1 (30 nmol/L). Relaxation to isoproterenol and forskolin were obtained. Vascular sensitivity (pD2) to isoproterenol was not different in the presence of endothelin-1 (7.6 +/- 0.3; n = 13) and phenylephrine (7.5 +/- 0.3; n = 11). The maximal relaxation (Emax) however, was doubled (P < 0.05) by endothelin-1 (42 +/- 5%), as compared with phenylephrine (23 +/- 4%). In the presence of endothelin-1, chelerythrine (protein kinase C inhibitor; 10 micromol/L) increased (P < 0.05) vascular sensitivity to isoproterenol (8.6 +/- 0.4, n = 7), but had no influence on the Emax. In contrast, in the presence of phenylephrine, pD2 was unaffected by chelerythrine, whereas the Emax to isoproterenol was increased (P < 0.05; 50 +/- 4%, n = 8). Vascular sensitivity and Emax to forskolin were similar in the presence of endothelin-1 and phenylephrine. In conclusion, endothelin-1 reduces vascular sensitivity to isoproterenol in a PKC-dependent pathway. The permissive effect of endothelin-1 appears to directly target the beta-adrenoceptor/G protein complex upstream of adenylate cyclase.
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PMID:Endothelin-1 limits vascular smooth muscle beta-adrenergic receptor sensitivity by a PKC-dependent pathway. 1450 40

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP1, EP2, EP3, EP4, and IP receptors. The EP4 receptor-specific agonist, 11-deoxy-PGE1, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP2 receptor agonist, butaprost, was without effect. PGI2 or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC50 values of 10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP4 receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.
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PMID:Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of endothelin-1 or basic fibroblast growth factor. 1496 6

Atherosclerosis is the primary ischaemic vascular condition underlying a majority of cardiovascular disease related deaths. Endothelin-1 is a vasoactive peptide agent upregulated in atherosclerosis and in conjunction with its G protein-coupled receptors exerts diverse actions on all cells of the vasculature in particular vascular smooth muscle cells (VSMC). The effects of endothelin-1 include cell proliferation, migration and contraction, and the induction of extracellular matrix components and growth factors. VSMC as the major component of the neointima in atherosclerotic plaques accordingly play a key role in atherogenesis. In this review we examine classic and novel signalling pathways activated by endothelin-1 in VSMC (including phospholipase C, adenylate cyclase, Rho kinase, transactivation of receptor tyrosine kinases, mitogen activated protein kinase cascades and beta-arrestin) and their likely impact on the development and progression of atherosclerosis.
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PMID:Endothelin-1 signalling in vascular smooth muscle: pathways controlling cellular functions associated with atherosclerosis. 1843 25

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells. Its synthesis, mainly regulated at the gene transcription level, involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1. The latter peptide can then be cleaved directly by an endothelin-converting enzyme (ECE) into ET-1 or reach the active metabolite through a two-step process involving chymase hydrolyzing big ET-1 to ET-1 (1-31), itself needing conversion to ET-1 by neprilysin (NEP) to exert physiological activity. ET-1 signals through two G protein-coupled receptors, endothelin receptor A (ETA) and endothelin receptor B (ETB). Both receptors induce an increase in intracellular Ca(2+), mainly from the extracellular space through voltage-independent mechanisms, the receptor-operated channels and store-operated channels. ET-1 also induces signaling through epidermal growth factor receptor transactivation, oxidative stress induction, rho-kinase, and the activation (ETA) or inhibition (ETB) of the adenylate cyclase/cyclic adenosine monophosphate pathway. Arterial vasoconstriction is mediated mainly by the ETA receptor. ET-1, via endothelium-located ETB, relaxes arteries or constricts vessels following activation of the same receptor type on the smooth muscle, where it can interact with ETA. In addition, ETB-dependent vasoconstriction seems more prominent in the venous vasculature. A better understanding of how ET-1 is synthesized and how ETA and ETB receptors interact could help design better pharmacological agents in the treatment of cardiovascular diseases where targeting the ET-1 system is indicated.
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PMID:Endothelin-1: Biosynthesis, Signaling and Vasoreactivity. 2745 Oct 97

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