Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Detection of ET-LI in porcine and human tissues in the present study revealed the presence of high levels in blood vessels, heart, airways, kidney, placenta, amnion and umbilical vessels. ET-1 was the predominant form in both porcine and human tissues, while evidence for additional occurrence of ET-3 was obtained in the porcine kidney and spinal cord. No evidence for presence of VIC or ET-2 was obtained in the studied porcine or human tissues. Immunohistochemical techniques revealed the presence of ET-LI in the amniotic membrane cells as well as in vascular endothelial cells. 2. Transient release of ET-LI from the porcine spleen was observed during endotoxin infusion and after a 2 min period of asphyxia. During endotoxin administration plasma ET-LI increased progressively and the presence of both ET-1 and big ET-1 in the plasma was shown. Short term sympatho-adrenal activation did not evoke ET-release, however. In man, high levels of ET-LI, indicating release, were observed in the amniotic fluid and umbilical plasma at birth. 3. Specific, high affinity ET receptors were demonstrated in human and porcine tissues. One main characteristic for ET binding was the extremely slow dissociation rate. The ET-1 selective ETA receptor was predominant in the porcine spleen and renal artery as well as in the human heart and umbilical arteries, whereas the ETB receptor predominated in the porcine renal medulla and the spinal cord and the human placenta. In the porcine and human lung a mixed population of ETA and ETB receptors seemed to be present. ET-1 but not ET-3 increased IP turnover in the spleen, while both ET-1 and ET-3 was effective in the lung, suggesting the same second messenger system for both receptor subtypes. Neither ET-1 nor ET-3 was observed to have any effect on the adenylate cyclase system. 4. ET-1 was extremely potent as a vasoconstrictor in the porcine kidney and spleen in vivo, while the effect in the femoral vascular bed was less pronounced. ET-3 was considerably less potent than ET-1 as vasoconstrictor in the kidney and the spleen. However, ET-1 and ET-3 acted equipotently as vasodilators in the bronchial circulation, suggesting opposite vascular effects in the different vascular beds. Big ET-1 caused only minor vasoconstriction. ET-1 was a potent constrictor agent of human coronary, pulmonary and umbilical vessels as well as of human bronchi in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical and functional characterization of endothelin peptides with special reference to vascular effects. 165 15

We studied whether endothelin (ET) isopeptides have any effects on adenylate cyclase activity in cultured bovine endothelial cells (ECs). Both ET-1 and ET-3 dose-dependently inhibited cAMP formation stimulated by forskolin and isoproterenol, although the inhibitory effect of ET-1 was less potent than that of ET-3. In contrast, ET-1 and ET-3 almost equipotently inhibited forskolin-stimulated cAMP formation in bovine EC pretreated with phosphoramidon, a putative ET-1 converting-enzyme inhibitor. These data suggest that endothelial ETB receptors are functionally coupled to adenylate cyclase, possibly via Gi protein.
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PMID:Endothelin subtype B receptors are coupled to adenylate cyclase via inhibitory G protein in cultured bovine endothelial cells. 750 32

To study signal transduction pathways of endothelin (ET) in human heart, we assessed, in isolated human right atria, the effects of ET-1 and ET-3 on inositol phosphate (IP) formation and on the adenylate cyclase/cyclic AMP system. In right atrial slices, ET-1 (10(-10)-10(-6)M) concentration-dependently increased [3H]IP accumulation and decreased 10-microM isoprenaline-induced or 1-microM forskolin-induced increases in cyclic AMP content. ET-3 was approximately 100 times less potent. The cyclic AMP-decreasing effect of ET-1 (10(-11)-10(-6)M) could also be demonstrated directly in adenylate cyclase assays in right atrial membranes; again, ET-3 was approximately 100 times less potent. We conclude that in human right atrium, ETA receptors couple to two different signal-transduction pathways: IP formation and inhibition of adenylate cyclase.
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PMID:Endothelin ETA-receptors couple to inositol phosphate formation and inhibition of adenylate cyclase in human right atrium. 751 68

We have studied whether endothelin (ET) isopeptides have any effects on adenylate cyclase activity via different guanyl nucleotide-binding proteins (G-proteins) in cultured rat vascular smooth muscle cells (VSMC) and bovine endothelial cells (EC). Northern blot analysis clearly demonstrated gene expression of ETA receptors in VSMC and ETB receptors in EC. ET-1 dose-dependently (10(-9)-10(-6) M) stimulated cAMP formation in VSMC, whose effect was inhibited completely by ETA receptor antagonist (BQ-123) but not by indomethacin or quinacrine. The ET-1-induced cAMP formation was additive with isoproterenol but not with cholera toxin. In contrast, ET-3 and ETB receptor agonist (BQ-3020) dose-dependently (10(-9)-10(-6) M) inhibited forskolin-stimulated cAMP formation in EC, whose effect was completely abolished by pertussis toxin. Cholera toxin ADP ribosylated 45- and 52-kilodalton proteins in VSMC, whereas pertussis toxin ADP ribosylated the 41-kilodalton protein in EC. These data suggest that, in addition to phospholipase C via Gq, ETA and ETB receptor subtypes are functionally coupled to adenylate cyclase, possibly via Gs in VSMC and Gi in EC, respectively.
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PMID:Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature. 767 93

In the mammalian iris sphincter smooth muscle, endothelins (ET) activate both adenylate cyclase and the polyphosphoinositide cascade, and the levels of cyclic AMP (cAMP) and inositol 1,4,5-trisphosphate (IP3) produced are species specific. Radioligand binding studies, using [125I]ET-1 and [125I]ET-3 and determination of changes in cAMP, IP3 and contraction due to the peptides revealed the existence of ETA and ETB receptor subtypes in this tissue. In rabbit sphincter, ETA receptors constitute about 80% of total ET receptor population and these are coupled to IP3 production and contraction. In bovine sphincter, ETB receptors constitute about 72% of the total ET receptors and these are coupled to cAMP formation. Thus, in rabbit sphincter: 1) ET-1 and ET-2, two potent ETA receptor agonists, induced IP3 production and contraction at a much higher rate than ET-3, a weak ETA agonist. The EC50 for contraction by ET-1, ET-2 and ET-3 were 40, 45 and 300 nM, respectively. 2) Sarafotoxin-S6c (SRTX-c), a selective ETB receptor agonist, had no effect on IP3 and contraction in this tissue. 3) D-Asp-L-Pro-D-Val-L-Leu-D-Trp (BQ-123), a selective ETA receptor antagonist, inhibited the above responses to ET. 4) ET and SRTX-c induced cAMP formation at a much lower rate than that of IP3 and contraction. In contrast, in the bovine sphincter: 1) ET and SRTX-c induced cAMP formation in a dose-dependent manner, the order of potency being SRTX-c > ET-3 congruent to ET-2 congruent to ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of iris sphincter smooth muscle endothelin receptor subtypes which are coupled to cyclic AMP formation and polyphosphoinositide hydrolysis. 813 49

1. The non-selective endothelin agonist, endothelin-1 (ET-1), and the selective ETB receptor agonist, sarafotoxin-S6c (SRTX-c), contracted guinea-pig isolated trachea in a concentration-dependent manner. The EC50 value for ET-1 (11 +/- 2.1 nM) was significantly higher than that of SRTX-c (3.2 +/- 0.21 nM) and the maximal developed tension due to SRTX-c was 42.8 +/- 2.3% higher than that produced by ET-1 (P < 0.05). 2. Pretreatment with the ETA antagonist, BQ-610, appreciably enhanced the developed tension due to ET-1 but not SRTX-c. Likewise, the cyclo-oxygenase inhibitor, indomethacin, markedly potentiated the contractile responses to ET-1, but not to SRTX-c. Combining BQ-610 with indomethacin was not more effective than either of them in augmenting ET-1-evoked tension. 3. ET-1 significantly increased cyclic AMP formation in the trachea in concentration- and time-dependent manners. A t1/2 value of 4.3 min, an EC50 value of 20 +/- 3 nM and a maximal cyclic AMP increment of 124% above the basal level, were obtained for ET-1. Similarly but less effectively, ET-3 (0.1 microM) increased cyclic AMP level (35 +/- 3.7% compared to 94 +/- 7.8% for the same concentration of ET-1). By contrast, SRTX-c did not alter the cyclicAMP level when applied in concentrations up to 1 microM. 4. Pre-incubation of the trachea with BQ-610 (1 microM) or indomethacin (1 microM) prevented cyclicAMP formation by either ET-1 or ET-3. 5. The results of the present study indicate a negative regulatory role mediated by the ETA receptor on the ETB-triggered mechanical response. This effect is likely to be mediated by activation of adenylate cyclase through a cyclo-oxygenase-dependent mechanism.
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PMID:Endothelins-induce cyclicAMP formation in the guinea-pig trachea through an ETA receptor- and cyclooxygenase-dependent mechanism. 876 74

By site-directed mutagenesis, three cysteine residues (amino acids 402, 403, and 405) in the carboxyl terminus of human endothelinB (ETB) were identified as potential palmitoylation sites. Substitutions of all of the three cysteine residues with serine gave an unpalmitoylated mutant, C2S/C3S/C5S. When expressed in Chinese hamster ovary cells, C2S/C3S/C5S was localized on the cell surface, retained high affinities to ET-1 and ET-3, and was rapidly internalized when bound to the ligand. However, unlike the wild-type ETB, C2S/C3S/C5S transmitted neither an inhibitory effect on adenylate cyclase nor a stimulatory effect on phospholipase C, indicating a critical role of palmitoylation in the coupling with G proteins, regardless of the G protein subtypes. Truncation of the carboxyl terminus including Cys403/Cys405 gave a deletion mutant Delta403 that was palmitoylated on Cys402 and lacked the carboxyl terminus downstream to the palmitoylation site. Delta403 did transmit a stimulatory effect on phospholipase C via a pertussis toxin-insensitive G protein but it failed to transmit an inhibitory effect on adenylate cyclase. These results indicated a differential requirement for the carboxyl terminus downstream to the palmitoylation site in the coupling with G protein subtypes, i.e. it is required for the coupling with Gi but not for that with Gq.
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PMID:Palmitoylation of human endothelinB. Its critical role in G protein coupling and a differential requirement for the cytoplasmic tail by G protein subtypes. 926 Nov 80

In the present study, we investigated the mechanisms underlying the differential effects of endothelins (ETs) in the rat trachea. Sarafotoxin-S6c (SRTX-c) and ET-3 were more potent spasmogens to rat tracheal strips than ET-1. The EC50 values were 12, 14.1 and 89.1 nM, respectively. Tension responses to ET-1 and ET-3, but not to SRTX-c, were enhanced by either indomethacin or the ET(A) blocker, BQ-610 (1 microM). In epithelium-intact tracheal rings, both ET-1 and ET-3 activated adenylate cyclase (AC) in a concentration-dependent manner. The activation by ET-1 of AC was significantly higher than that of ET-3. Thus, EC50 values for ET-1 and ET-3 were 71 and 200 nM, and maximal cAMP increments were 196% and 62% above baseline, respectively. SRTX-c, up to 1 microM, did not alter basal cAMP level. Mechanical removal of the epithelium neither had an effect on AC activation by ET-1 or ET-3, nor did it alter the inability of SRTX-c to modulate AC activity. Conversely, pre-incubation of tracheal strips with indomethacin (1 microM) virtually ablated the increments in cAMP by the ETs. Likewise, BQ-610 attenuated AC activation, concentration-dependently (IC50=28.2 nM). Taken together, the present study suggests that ET(A) receptors, from non-epithelial source, are functionally-linked to AC activation via a prostanoid-dependent pathway. This ET(A)-initiated cascade acts to negatively regulate muscle contraction. Such a cross-talk between ET signals most likely accounts for variation of tension responses to ET homologs.
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PMID:Non-epithelial endothelin-A receptors activate adenylate cyclase in rat trachea: biochemical mechanisms and physiological implications. 932 32

We demonstrate that the human endothelin-B (ETB) receptor incorporates [3H]palmitic acid. Mutation of three putative palmitoylated cysteine residues (amino acids 402, 403 and 405) in the carboxyl terminus into serine residues (C2/3/5S) completely prevented palmitoylation of ETB. When expressed in CHO cells, C2/3/5S was localized on the cell surface, retained high affinity for ET-1 and ET-3, and was rapidly internalized when bound to the ligand. However, unlike the wild-type ETB, C2/3/5S transmitted neither an inhibitory effect on adenylate cyclase nor a stimulatory effect on phospholipase C, indicating a critical role of palmitoylation in the coupling with G-proteins, regardless of the G-protein subtype. Truncation of the carboxyl terminus, including all or a part of the three cysteine residues, gave palmitoylation-negative and -positive deletion mutants, delta 402 and delta 403. Despite the absence of the cytoplasmic tail, both delta 402 and delta 403 showed essentially the same features as C2/3/5S, except that delta 403 did transmit a stimulatory effect on phospholipase C via a pertussis toxin-insensitive G-protein, most likely a member(s) of the Gq family. These results indicated a differential requirement for the carboxyl terminus downstream from the palmitoylation site in the coupling with G-protein subtypes, i.e., it is required for the coupling with Gi but not for that with Gq.
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PMID:Cysteine residues in the carboxyl terminal domain of the endothelin-B receptor are required for coupling with G-proteins. 959 45

The role of cAMP and cAMP-dependent protein kinase A (PKA) in endothelin (ET)-stimulated migration of human neutrophils was studied. Endothelins caused an increase in neutrophil migration when they were applied in low (nanomolar) concentrations; stimulation of migration was either predominantly chemokinetic (ET-1) or chemotactic (ET-2, ET-3). All endothelins, at concentrations which gave maximal stimulation of migration, caused an increase of cAMP level. Two inhibitors of adenylate cyclase, MDL-12330A and SQ-22536, completely inhibited migration activated by ET-1, ET-2 or ET-3, indicating that cAMP generation played a decisive role in endothelin-activated migration. The role of PKA in endothelin-activated migration was considered. Two specific antagonists of PKA strongly inhibited endothelin-activated migration. KT-5720, an inhibitor of PKA, also inhibited ET-activated migration, but only when electroporated cells were used. The results suggest that the effect of cAMP on endothelin-activated migration was mediated by PKA.
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PMID:The role of cyclic AMP and protein kinase A in stimulation of neutrophil migration by endothelins. 984 Apr 19


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