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Query: UNIPROT:P06889 (Mol)
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Previous studies have shown the effects of angiotensin II (Ang II) in teleosts, and Ang II-binding sites have also been localized in tissues from rainbow trout. The purpose of this study was to extend these findings and to provide an analysis of Ang II receptor (Ang II-R) isoforms in three tissues obtained from European eel (Anguilla anguilla). Ang II-Rs were identified in eel liver, kidney and intestine membranes by the binding of either 0.5 nmol human 125I-labelled Tyr4-Ile5-Ang II/l or increasing concentrations (1-120 nmol/l) of [3,5-3H]Tyr4-Ile5-Ang II. Using an isoelectric focusing technique, two Ang II-binding sites were identified in liver membranes. These migrated to isoelectric points (pI values) 6.5 and 6.7. Seventy per cent of binding to both sites was displaced by a 10,000-fold excess of unlabelled human Ang II. In both whole plasma membranes and brush border membranes from intestine, only one form of the Ang II-R was found, with pI 6.5 and high affinity (Kd = 3.4 nmol/l) for the [3,5-3H]Tyr4-Ile5-Ang II. Similarly, only the isoform focusing at pI 6.5 was observed in renal tubular epithelial brush border membranes. Reduction of disulphide bridges with dithiothreitol significantly enhanced Ang II binding to the isoform at pI 6.5 in liver (P < 0.05) and kidney (P < 0.01), while in liver the binding to the isoform of pI 6.7 was significantly reduced (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1994 Feb
PMID:Angiotensin II receptor subtypes in eel (Anguilla anguilla). 818 15

The angiotensin II (Ang II)-binding sites in rat adrenal gland membranes were characterized using 125I-radiolabelled Ang II. While Scatchard analysis identified a single population of Ang II receptor sites, isoelectric focusing (IEF) on polyacrylamide gels revealed four peaks of specific Ang II binding which migrated to isoelectric points (pI values) 6.8, 6.7, 6.5 and 6.3. In binding assays in the presence of an excess of the Ang II receptor AT1 subtype antagonist DuP 753, a monophasic dose-dependent displacement of 125I-labelled Ang II binding by the Ang II receptor AT2 subtype antagonist CGP42112A was observed, and vice versa. In this system, reduction of disulphide bridges using 1 mmol dithiothreitol (DTT)/l markedly increased the number of binding sites in the adrenal zona glomerulosa without affecting receptor affinity. Using IEF, it was found that both DuP 753 and CGP42112A were able to reduce specific binding of each of the four peaks to some extent. However, the predominant effect of DuP 753 was to reduce the labelling of the isoform at pI 6.7 substantially, while CGP42112A significantly inhibited the specific 125I-labelled Ang II binding to the pI 6.3 isoform. When DuP 753 and CGP42112A were used together, specific binding of 125I-labelled Ang II to the isoforms of pI values 6.8, 6.7 and 6.3 was completely eliminated. These data suggest that the four peaks of specific binding found may be composed of different isoforms of both AT1 and AT2 receptor subtypes and that the Ang II receptor isoforms which migrated to pI 6.7 and pI 6.3 are predominantly composed of AT1 and AT2 receptor subtypes respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1993 Aug
PMID:Angiotensin II receptor isoforms in the rat adrenal gland: studies with the selective subtype antagonists DuP 753 and CGP42112A. 824 Jun 73

1. Specific 125I-Sar1, Ile8-Angiotensin II (125I-Sar1, Ile8-AII) binding sites in bovine retinal microvessels were investigated using the quantitative receptor autoradiographic method with pellet sections. 2. A quantitation was made with the computerized radioluminographic imaging plate system, a newly developed and highly sensitive method. Binding characteristics of the retinal microvessels were compared with those of the cerebral microvessels and the retinal macrovessels. 3. We isolated microvessels from the bovine retina and bovine cerebral cortex using the method composed of two-size sievings and high-speed homogenization with a Polytron. The isolated microvessels were composed of capillaries, and the retinal macrovessels contained vessels with smooth muscle. 4. There were specific binding sites for 125I-Sar1, Ile8-AII which were single and of a high affinity, in both the cerebral and the retinal microvessels and the retinal macrovessels. There were no differences in affinity between the vessels, but the retinal microvessels did have a higher density of binding sites than the cerebral microvessels. 5. The method we used is simple and sensitive for detecting and characterizing 125I-Sar1, Ile8-AII binding sites in retinal capillaries. Knowledge of the existence of large numbers of specific binding sites, candidates of physiologically active angiotensin II receptors, aids with understanding the regulatory roles of angiotensin II in the blood-retinal barrier.
Cell Mol Neurobiol 1993 Jun
PMID:Quantitative receptor autoradiographic analysis for angiotensin II receptors in bovine retinal microvessels: quantitation with radioluminography. 824 87

To investigate the contribution of the cardiac renin-angiotensin system to ventricular dilatation after myocardial infarction, we examined the effects of 3-week treatments with an angiotensin converting enzyme inhibitor, delapril, and a selective angiotensin II type 1 (AT1) receptor antagonist, TCV-116, on haemodynamics and ventricular angiotensin II contents in myocardial-infarcted rats. TCV-116 reduced mean aortic pressure, and prevented the increase of right and left ventricular weight, left ventricular end-diastolic pressure and volume of myocardial-infarcted rats, to a similar extent to delapril. Thus, AT1 receptor-mediated action of angiotensin II plays a central role in the development of ventricular dilatation. Angiotensin II contents in the right and non-infarcted left ventricles (6.0 +/- 1.0 and 5.9 +/- 0.7 pg/g tissue, respectively, mean +/- S.E.M.) of myocardial-infarcted rats were not different from those of sham-operated rats. However, angiotensin II contents in the infarcted scar (21.7 +/- 3.5 pg/g) of myocardial-infarcted rats were 4.2-fold higher than those in the left ventricle of sham-operated rats. Delapril reduced angiotensin II contents in the right and non-infarcted left ventricles, and the scar by 48, 81 and 60%, respectively, but did not reduce plasma angiotensin II in myocardial-infarcted rats. TCV-116 also decreased angiotensin II in the right and non-infarcted left ventricles by 57 and 56%, respectively, while increased plasma angiotensin II by 4.3-fold. Thus, the prevention of ventricular dilatation by these two agents was associated with the decrease in ventricular angiotensin II contents. These observations suggest that the cardiac renin-angiotensin system rather than the circulating system may play an important role in ventricular dilatation after myocardial infarction.
J Mol Cell Cardiol 1993 Nov
PMID:Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarcted rats. 830 70

A 2046-base pair cDNA clone, homologous to mammalian angiotensin (AT) AT1 receptors, was isolated from a library prepared from adrenal glands of the domestic turkey (Meleagris gallopavo). Sequence analysis of the cDNA insert in clone pTAT2' reveals a 1077-base pair open reading frame predicting a 359-amino acid protein approximately 75% homologous to mammalian AT1 receptors. Saturation radioligand binding studies performed in membranes of COS-7 cells transfected with pTAT2' show high affinity specific binding of 125I-angiotensin II, with a Kd of 172 pM. The rank order of affinities for a series of ligands determined by competition binding studies is angiotensin II > or = [Sar1,Ile8]-angiotensin II > angiotensin III approximately [Sar1,Ala8]-angiotensin II approximately CGP42112A > angiotensin I > Dup753 > PD123177. This rank order of affinity series differs substantially from that for mammalian AT1 receptors and AT2 binding sites. Angiotensin II (100 nM) can stimulate inositol phosphate production similarly in COS-7 cells transfected with pTAT2' and in COS-7 cells transfected with the AT1a receptor cDNA pCa18b. This response in pTAT2'-transfected cells is not attenuated in the presence of 30 microM Dup753. In contrast, this concentration of antagonist attenuates > 90% of the inositol phosphate response to angiotensin II in COS-7 cells transfected with the rat AT1a receptor cDNA. These results demonstrate an avian structural homologue of mammalian AT1 receptors possessing distinct pharmacological properties with both peptide and nonpeptide AT receptor ligands.
Mol Pharmacol 1993 Jul
PMID:A cloned angiotensin receptor isoform from the turkey adrenal gland is pharmacologically distinct from mammalian angiotensin receptors. 834 Dec 66

The study investigates the change in angiotensinogen (Aogen), angiotensin I (AngI) and renin plasma concentration after nephrectomy and adrenalectomy. The aim of the study was to elucidate the mechanisms that are involved in the up regulation of the Aogen plasma levels after nephrectomy and the contribution of the adrenals. Rats were treated with the beta 1-selective adrenoceptor blocker, atenolol, and with the angiotensin antagonist, DuP 753 in order to inhibit renal renin release and to check whether the increase in plasma Aogen after nephrectomy is mediated by angiotensin (AngII), respectively. The plasma Aogen levels increase approx. 5-fold 24 h after nephrectomy. This increase is significantly reduced in the presence of atenolol. After nephrectomy plus adrenalectomy there is a maximal increase of 60% in plasma Aogen levels 8 h after surgery and a subsequent decline. In the presence of atenolol this increase is even smaller. In contrast after adrenalectomy the plasma Aogen levels continuously declined. In the presence of atenolol the plasma Aogen levels were approx. 20% higher at time 0 but declined with the same slope as after adrenalectomy without atenolol treatment. Treatment with DuP 753 caused an almost complete inhibition of the increase in Aogen plasma levels after nephrectomy. Significantly higher Aogen levels were found only after 24 h. At time 0, immediately after nephrectomy the plasma AngI levels were increased compared to the respective control rats. Significantly higher AngI values (P < 0.05) could also be observed in nephrectomized rats and in nephrectomized plus adrenalectomized rats at time 0 in the presence and absence of atenolol and DuP 753, respectively. In contrast after adrenalectomy alone the AngI levels at time 0, were not different from those of the controls. Subsequently the AngI levels increased at a similar rate as after adrenalectomy in the presence of atenolol. These findings suggest that the increase in plasma Aogen after nephrectomy is essentially mediated by AngII via an adrenal mechanism. It seems likely that this process is triggered by renin released during surgery. The increased renin release after adrenalectomy that is responsible for the increased degradation of Aogen seems not to be mediated by a sympathetic stimulation of the renal beta 1-adrenoceptors.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Changes in the renin-angiotensin system after nephrectomy and adrenalectomy. 848 50

Angiotensin II (AII) binding sites were characterized in human myometrium membrane preparations. The sites were saturable and of high affinity (Kd of 0.09 nM and Bmax of about 200 fmol/mg of protein). PD 123319 completely inhibited 125I-AII binding, with an IC50 of 30 nM, whereas L-158,809 (1 microM) had no significant effect on 125I-AII binding. These results indicate that human myometrium contains almost exclusively the AT2 receptor subtype. Association and dissociation studies performed with 125I-AII on human myometrium membranes revealed that AII had a very high affinity for AT2 receptors, with a Kd of 0.01 nM (association rate constant K1 = 1.056 x 10(12) mol-1 min-1; dissociation rate constant K2 = 0.003 min-1). The photoactivable AII analogue [Sar1, Val5, D-Phe8(N3)]AII displayed a high affinity for AT2 receptors (IC50 of 0.18 nM), but its radioiodinated form showed poor efficiency in photoaffinity labeling experiments. A newly synthesized photoactivatable analogue of AII, [Sar1, p-benzoyl-Phe8]AII, (AII-Bpa), also displayed a high affinity for AT2 receptors of human myometrium (IC50 of 0.3 nM). Photoaffinity labeling experiments were performed with 125I-AII-Bpa, and a high yield (70%) of covalent incorporation to human myometrium membranes was obtained upon photolysis. Covalently labeled receptors were solubilized, denatured, and subjected to polyacrylamide gel electrophoresis. Autoradiography of the polyacrylamide gel revealed a single band, of 68 kDa, and the labeling of this band was completely abolished in the presence of 1 microM PD 123319, indicating selective labeling of the AT2 receptor subtype. These results demonstrate that AII-Bpa is a very efficient tool for selective photoaffinity labeling of the AT2 receptor.
Mol Pharmacol 1993 May
PMID:Photoaffinity labeling of subtype 2 angiotensin receptor of human myometrium. 850 25

A protein, Bm91, which was first identified as a protective vaccine antigen from the tick Boophilus microplus, has regions of very strong amino acid sequence similarity to mammalian carboxydipeptidases or angiotensin converting enzymes (ACE; E.C. 3.4.15.1). This protein is now shown to share many biochemical and enzymatic properties with mammalian carboxydipeptidases. It is enzymatically active in a conventional assay for ACE using hippuryl-Gly-Gly as substrate. The hydrolysis of the C-terminal nonapeptide of the insulin B chain proceeds by sequential removal of carboxy-terminal dipeptides. The similarities extend to the dependence of activity on pH and added salt. Bm91 is inhibited by two well-characterized inhibitors of the mammalian enzymes, the drug Captopril and a nonapeptide, and the inhibition occurs in similar concentration ranges to those effective with the mammalian enzymes. However, the natural substrates of the tick enzyme are unknown. Angiotensin I itself is a poor substrate and the enzyme's natural substrates are likely to be one or more of the pharmacologically active peptides occurring in insects and arthropods.
Insect Biochem Mol Biol 1995 Oct
PMID:Carboxydipeptidase from Boophilus microplus: a "concealed" antigen with similarity to angiotensin-converting enzyme. 854 86

The NPXnY motif is involved in the internalization process of several types of receptors, including lipoprotein receptors and G protein-coupled receptors. We replaced Tyr302 with either phenylalanine or alanine in the NPLFY site of the human angiotensin II receptor type 1 and determined the pharmacological properties of the resulting mutant receptors. Competitive binding experiments revealed that COS-7 cells transfected with either the wild-type or mutant receptors expressed approximately the same amount of high affinity binding sites (Bmax 70,000 sites/cell and Kd approximately 2 nM). Photoaffinity labeling of both native and mutant receptors revealed apparent molecular masses of 110 kDa. Incubation of transfected cells with 0.2 nM [125I]Ang II at 37 degrees revealed an efficient internalization of the wild-type receptor and the mutant receptors, although the mutant receptors were internalized at a slower rate. Interestingly, however, the transmembrane signaling was severely impaired in transfected cells expressing mutant receptors. No significant production of inositol-1,4,5-trisphosphate was observed when these cells were challenged for 3 min with a concentration of angiotensin II as high as 1 microM. This is in contrast to the dose-dependent stimulation of inositol-1,4,5-trisphosphate production in cells expressing the wild-type receptor. Thus, our results show that the Tyr302 in the NPXnY motif of the human angiotensin II receptor type 1 is not essential for agonist binding properties or for internalization of the receptor but plays an important role in transmembrane signaling.
Mol Pharmacol 1996 Jan
PMID:The tyrosine within the NPXnY motif of the human angiotensin II type 1 receptor is involved in mediating signal transduction but is not essential for internalization. 856 17

Recent studies have shown that G proteins are a potential regulatory site in the transmembrane signaling cascade. The aim of this study was to examine the effects of prolonged agonist exposure on expression of the Gq class of G protein alpha subunits (G alpha q/G alpha 11) in cultured rat vascular smooth muscle cells (VSMC). Treatment with 100 nM angiotensin II (Ang II) led to a substantial sustained down-regulation of cellular levels of immunologically detectable G alpha q/G alpha 11 by 50% within 6 hr. The effect of Ang II was dose dependent with an EC50 of 2 nM and was specifically blocked by the vascular type-1 Ang II receptor-specific antagonist losartan. The Ang II-induced reduction in cellular levels of G protein alpha subunits was specific for G alpha q/G alpha 11. The calcium ionophore ionomycin or activators of ubiquitous protein kinases (phorbol-12-myristate-13-acetate, forskolin, and 8-bromo-cGMP) did not mimic the effects of Ang II. However, [Arg8]vasopressin also induced a significant loss in cellular G alpha q/G alpha 11 levels. Ang II-induced G alpha q/G alpha 11 down-regulation was reversed by prevention of cellular receptor processing with phenylarsine oxide or chronic potassium depletion. The effects of Ang II on G alpha q/G alpha 11 levels were inhibited when protein kinase C activity was abolished. G alpha q mRNA levels were down-regulated by 30% after 4-hr incubation with Ang II, in part by transcriptional regulation. Although a short term vasopressin pretreatment had no effect on inositol-1,4,5-trisphosphate (IP3) generation in response to subsequent Ang II stimulation, a partial heterologous desensitization of the IP3 response was induced after a long term vasopressin pretreatment, which concurrently down-regulated cellular G alpha q/G alpha 11 levels. Homologous desensitization of IP3 generation on a second Ang II stimulation was observed after both a short and long term Ang II pretreatment. In conclusion, prolonged exposure to Ang II induces down-regulation of cellular G alpha q/G alpha 11 levels in intact VSMC. The effect of Ang II appears to be mediated by the signaling pathway sensitive to inhibition of receptor processing. The present study raises the possibility that agonist-induced G alpha q/G alpha 11 down-regulation participates in the mechanism of long term desensitization of the G alpha q/G alpha 11-mediated signaling system in VSMC.
Mol Pharmacol 1996 Jan
PMID:Prolonged exposure to agonist results in a reduction in the levels of the Gq/G11 alpha subunits in cultured vascular smooth muscle cells. 856 18


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