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At least 19 recordsLinked to original sources
PubMed2006

A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice.

The steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (>85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.

Animals↗
PubMedDate not supplied

Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.

Endothelin-1 was initially identified as a 21-residue potent vasoconstrictor peptide produced by vascular endothelial cells, but was subsequently found to have many effects on both vascular and non-vascular tissues. The discovery of three isopeptides of the endothelin family, ET-1, ET-2 and ET-3, each possessing a diverse set of pharmacological activities of different potency, suggested the existence of several different endothelin receptor subtypes. Endothelins may elicit biological responses by various signal-transduction mechanisms, including the G protein-coupled activation of phospholipase C and the activation of voltage-dependent Ca2+ channels. Thus, different subtypes of the endothelin receptor may use different signal-transduction mechanisms. Here we report the cloning of a complementary DNA encoding one subtype belonging to the superfamily of G protein-coupled receptors. COS-7 cells transfected with the cDNA express specific and high-affinity binding sites for endothelins, responding to binding by the production of inositol phosphates and a transient increase in the concentration of intracellular free Ca2+. The three endothelin isopeptides are roughly equipotent in displacing 125I-labelled ET-1 binding and causing Ca2+ mobilization. A messenger RNA corresponding to the cDNA is detected in many rat tissues including the brain, kidney and lung but not in vascular smooth muscle cells. These results indicate that this cDNA encodes a 'nonselective' subtype of the receptor which is different from the vascular smooth muscle receptor.

Amino Acid Sequence↗
PubMed1993

Molecular characterization and regulation of the human endothelin receptors.

Endothelin receptors (ETRs) are distributed throughout a variety of tissues. Two human cDNAs were identified which encode distinct ETR proteins. One cDNA encoded a 427-amino acid protein that shared 91% identity to rat ETAR. The second cDNA encoded a 442-amino acid protein that was 88% identical to rat ETBR. Ligand binding studies of the cloned receptors expressed in COS cells confirmed that they were pharmacologically ETAR and ETBR subtypes; although the selective antagonist BQ123 showed a potency similar to ET-3 in displacing 125I-ET-1 binding to ETAR. This observation contrasts with rat ETAR pharmacology where BQ123 has a 100-fold higher affinity than ET3. Chinese hamster ovary cells expressing the human ETAR displayed equal potencies in displacing 125I-ET-1 binding, which indicates that rat and human ETAR are pharmacologically distinct. Electrophysiological studies of both ETRs expressed in Xenopus oocytes revealed that they are functional. Northern analysis indicated that the two ETRs are differentially expressed in many tissues. Marmosets maintained on a high fat/high cholesterol diet exhibited 3-fold increase in ETBR mRNA levels with little change in ETAR mRNA levels. Availability of cDNA clones for ETR subtypes can open avenues for future analysis of their role in pathophysiology of various diseases.

Amino Acid Sequence↗
PubMed1999

Structural basis of the function of endothelin receptor.

Endothelin receptor is a good model for analysis of the function of heptahelical G-protein coupled receptor. In ligand binding to the heptahelical receptor, the receptor has two functions, i.e. 'message' and 'address' functions. Each function has been assigned to different domain of the receptor. A different part of the ligand structure also corresponds to each domain of the receptor. Classically, classification of receptor has been done according to the difference of address domain, i.e. affinity difference of the receptor. However, present results predict that the classification of receptor is also possible according to the message domain. After stimulation of ET receptor by a ligand, the receptor transmits a signal to G-protein. Several kinds of G-proteins can possibly be activated. Different structural domains of the receptor are assigned to the coupling of the different Galpha-protein. Activated G-protein transmits the message to effector. Each Galpha-protein acts on different target molecules, resulting in different responses. However, the activation of each Galpha-protein presumably depends on its intracellular level. Even if the same receptor is activated with the same ligand, resulting final response is different from cell to cell. Therefore, classification of receptor according to the function of the receptor is difficult.

Animals↗
PubMed1991

Purification and characterization of bovine lung endothelin receptor.

Endothelin receptor was purified from bovine lung by a rapid and simple two-step procedure: 1) solubilization with the detergent 3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate and digitonin and 2) affinity chromatography using biotinylated endothelin and avidin-agarose. Starting from 3.5 kg of bovine lung, about 200 micrograms of pure receptor were obtained. Microsequencing of tryptic fragments of the purified protein revealed a high sequence similarity with the rat endothelin ETB receptor that has very recently been cloned by expression cloning and shown to be nonselective in terms of the ligand specificity. Purification of the receptor in the presence of low (1 mM) and high (50 mM) concentrations of EDTA yielded, as a major form, 34- and 52-kDa species, respectively, indicating that the lower Mr species (34 kDa) is a proteolytic product of the 52-kDa species. Interestingly, this metal proteinase-mediated limited proteolysis did not affect the ligand binding properties of the receptor.

Amino Acid Sequence↗
PubMed1995

Differentiation of embryonal carcinoma cells to a neural or cardiomyocyte lineage is associated with selective expression of endothelin receptors.

Endothelins (ETs) were initially characterized as potent vasoactive peptides acting through at least two distinct receptors, ETA and ETB. Subsequently, their significant growth- and hypertrophy-promoting properties in cardiac and other cells were recognized. We investigated the expression of endothelin receptors during differentiation of a pluripotential embryonal carcinoma cell line (P19) to a cardiomyocyte or a neural lineage. These cells resemble those of the inner cell mass of the blastocyst, and their differentiation is believed to closely mimic critical events in early embryogenesis. Differentiation of P19 to a cardiomyocyte lineage, by aggregation and exposure to dimethyl sulfoxide resulted in induction of ETA receptors as demonstrated by radioligand binding studies, Northern blotting, and reporter gene analysis. Moreover, the P19 differentiated to a cardiac lineage responded to ET-1 with a 3-fold increase in the secretion of atrial natriuretic peptide. In contrast, differentiation to a neural lineage, by aggregation and exposure to retinoic acid, was associated with the induction of predominantly ETB. Therefore, selective differentiation of the P19 led to the differential expression of endothelin receptors in a pattern consistent with that observed in normal myocardial and neural tissue. The induction of endothelin receptors in a model system of early embryogenesis provides strong support for the critical role of this peptide/receptor family in differentiation and development. As well, this model system is well suited for the study of the mechanisms controlling endothelin receptor expression during differentiation.

Animals↗
PubMedDate not supplied

Cloning and expression of a cDNA encoding an endothelin receptor.

Endothelins are a newly described peptide family consisting of three peptides (ET-1, ET-2 and ET-3) which are the most potent vasoconstrictive peptides known. They are crucial in the regulation of vascular smooth muscle tone. The diverse functions of endothelins are thought to be mediated by interaction with many different receptors coupled to the inositol phosphate/calcium ion messenger pathway. However, because of the structural resemblance of the three peptides, the presence and nature of multiple endothelin receptors remain to be elucidated. We report here the cloning of a complementary DNA encoding a bovine endothelin receptor, which has a transmembrane topology similar to that of other G protein-coupled receptors and shows specific binding, with the highest selectivity to ET-1 in animal cells transfected with the cloned cDNA. This receptor messenger RNA is widely distributed in the central nervous system and peripheral tissues, particularly in the heart and lung. Our results support the view that there are other receptor subtypes.

Amino Acid Sequence↗
PubMed2003

Enrasentan, an antagonist of endothelin receptors.

Endothelins are powerful vasoconstrictor agents produced by endothelial cells and identified by Yanagisawa et al. in 1988. Two types of receptors for endothelins have been identified: ET(A) receptors are located on smooth muscle cells of the vascular wall and are responsible for endothelin-induced vasoconstriction while ET(B) receptors are located on endothelial cells and induce these cells to release NO and prostacyclin. Moreover, these peptides not only cause a potent and prolonged vasoconstriction but are also known to enhance cell proliferation and to stimulate extracellular matrix accumulation. High levels of plasma or tissue endothelins have been found in patients with heart failure, diabetes, stroke, primary pulmonary hypertension, liver cirrhosis and other diseases. Given these effects of endothelins, blocking their receptors might be a new way to reduce blood pressure and to treat other illnesses. Accordingly, many endothelin antagonists have been developed and evaluated in animals and humans. Enrasentan is a mixed ET(A) and ET(B) receptor antagonist with a higher affinity for ET(A) receptors, although it cannot be considered a selective antagonist. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan has been added to conventional treatment in patients with heart failure (NYHA Class 2-3) and no addictive effect of the drug has been observed. This is in contrast with results obtained in animal models and still has not been explained. In conclusion, many possible clinical applications can be suggested for this drug, but further studies are necessary to better evaluate its therapeutic efficacy.

Animals↗
PubMed1996

Human astrocytoma U138MG cells express predominantly type-A endothelin receptor.

Endothelin-1 (ET-1) binding to human astrocytoma U138MG cells was time-dependent, and bound [125I]ET-1 was difficult to dissociate. The B(max) and Kd values of [125I]ET-1 binding were 70 fmol/mg and 0.07 nM, respectively. Interestingly, different from other astrocytoma cells and astrocytes, the U138MG cells expressed predominantly ETA receptor as shown by RT-PCR results and binding studies. ET-1, FR139317, BQ123, PD142893 and Ro46-2005 inhibited specific [125I]ET-1 binding with Ki values of 0.10, 0.53, 4.3, 22, and 320 nM, respectively. ETB selective ligands ET-3 and IRL1620 were much less potent. The inhibitory effects of antagonists BQ123 and PD142893 on [125I]ET-1 binding diminished following the incubation time. ET-1 binding caused a modest stimulation in phosphatidylinositol hydrolysis with an EC50 value of 24 nM. In comparison to the human U373MG cells, ET-1-induced receptor internalization in U138MG cells was less efficient with 42% of bound ET-1 internalized after 30 min of incubation. These results imply that human astrocytoma cells/astrocytes are able to express either ETA or ETB receptor under different pathophysiological conditions.

Astrocytoma↗
PubMed1996

Endothelin receptor synthetic N-terminal fragment interacts with the receptor itself.

Endothelin binds to receptors belonging to the family of G-protein-coupled receptors with an N-terminal extracellular domain that is suspected to be part of the binding site. We have synthesized different peptides of this N-terminal extracellular domain and analyzed the increase in calcium concentration ([Ca2+]i) induced by these peptides in the MEG-01 cell line and their influence on the ET-1 concentration-effect response. Nt (20-79) exhibited a partial agonistic effect on [Ca2+]i and blunted the functional response of ET-1 in MEG-01 cells, but was not able to compete with radiolabeled ET-1 binding. The agonist effect was inhibited by the ET receptor antagonists PD 142893 and BQ123, suggesting an interaction between Nt (20-79) and the ETA receptor at a site that could be different from the one of ET-1.

Amino Acid Sequence↗
PubMed2000

Internalization of type-A endothelin receptor.

Endothelins (ETs) are 21 amino acid peptides which bind to ET(A)- and ET(B)-receptors to evoke diverse physiological responses. This report studies the internalization of ET(A)-receptor in Chinese hamster ovary (CHO) cells which were stably transfected with ET(A)-receptor cDNA. ET-1 binding induced ET(A) internalization in a time-dependent manner with 40% of ET(A)-receptors internalized at 37 degrees C after 30 min. To localize internalized ET(A)-receptor, cells were immunostained using a polyclonal antibody against the extracellular loop between IV and V transmembrane segments of the ET(A)-receptor. To examine the fate of internalized ET-1, cells were treated with 10 nM biotinylated ET-1 coupled with Texas Red-labeled streptavidin. In the absence of ET-1, a majority of ET(A) was localized on the surface of cells. After ET-1 treatment for 60 min, internalized ET(A)-receptors were localized in a perinuclear structure. ET-1 remained bound to ET(A)-receptor after internalization for up to 60 min and then dissociated from the receptor. After dissociation, ET-1 possibly became degraded and ET(A) recycled back to the cell surface. Protein kinase inhibitors such as KT5926 and staurosporine partially inhibited ET(A)-receptor internalization. The results of this study may facilitate the understanding of pathways involved in ET-1-induced receptor internalization.

Animals↗
PubMed1997

Nonpeptide endothelin receptor antagonists. IX. Characterization of endothelin receptors in guinea pig bronchus with SB 209670 and other endothelin receptor antagonists.

In this study the endothelin (ET) receptors mediating contractions produced by ET-1, ET-3 and the selective ET(B) ligands sarafotoxin 6c (S6c) and BQ-3020 in guinea pig bronchus were investigated using SB 209670, a nonpeptide, mixed ET(A)/ET(B) receptor antagonist, and the peptide ET receptor antagonists BQ-123 (ET(A) receptor-selective), BQ-788 (ET(B) receptor-selective) and RES-701 (ET(B) receptor-selective). SB 209670 (10 microM) antagonized concentrations induced by ET-1 (pK(B) = 6.1). In contrast, BQ-788 (10 microM) and BQ-123 (10 microM), either alone or in combination, were without significant effect on ET-1 concentration-response curves. SB 209670 (10 microM) and BQ-788 (10 microM) antagonized S6c concentration-response curves with pKB values of 6.6 and 5.5, respectively, whereas RES-701 (10 microM) and BQ-123 (10 microM) were without effect. SB 209670 (10 microM) was about a 10-fold less potent antagonist of contractions produced by ET-3 (pK(B) = 5.4) than of those elicited by S6c. BQ-788 (10 microM), RES-701 (10 microM) and BQ-123 (10 microM) were without effect on ET-3 concentration-response curves. BQ-788 (10 microM) had similar potencies for inhibition of contractions induced by S6c (pK(B) = 5.8) and BQ-3020 (pK(B) = 6.25). These data indicate that contractions induced by ET-1, ET-3, S6c and BQ-3020 in guinea pig bronchus appear to be mediated predominantly via stimulation of ET(B) receptors. However, these receptors are not very sensitive to the standard ET(B) receptor antagonists BQ-788 and RES-701, which suggests that responses produced by these ligands in this tissue involve activation not of the classical ET(B) receptor, but rather of an atypical ET receptor population. The results also provide additional evidence that the potencies of ET receptor antagonists depend upon the specific ET agonist.

Animals↗
PubMed1989

Solubilization and identification of human placental endothelin receptor.

Endothelin-1 (ET-1) receptor was identified on the membranes from human placenta and 66% of original binding activity in the membranes was solubilized with 0.75% (w/v) CHAPS. Binding studies of the solubilized membranes using 125I-ET-1 indicated the presence of a single class of high-affinity binding sites with an apparent Kd of 760 pM and a Bmax of 1.8 pmol/mg of protein. The binding was inhibited by addition of unlabeled ET-1 and ET-3 in dose dependent manner. The Ki values of solubilized membranes were 84 pM for ET-1 and 250 pM for ET-3, whereas particulate membranes had weaker affinities (Ki = 410 pM for ET-1, 2500 pM for ET-3). Calcium channel blockers such as nicardipine, verapamil and diltiazem did not affect the binding of 125I-ET-1. Affinity labeling of the particulate and solubilized membranes with CHAPS revealed a specific binding protein with a Mr of 32,000.

Autoradiography↗
PubMed2002

Effect of castration on endothelin receptors.

Endothelin (ET) plays a pivotal role in the pathogenesis of cell growth disorders such as cancer. Atrasentan (ABT-627), a selective antagonist for the ET receptor A (ET(A)), has shown benefit in controlling disease progression in men with hormone refractory prostate cancer who have undergone aggressive hormone ablation therapy. It is not known how hormone ablation affects ET-binding sites, although ET-1 and ET(A) expression are found to be elevated in prostate cancer patients. In this study, we examined the effect of castration on ET receptor binding in male beagle dogs. Three dogs were surgically castrated and another three sham-operated. The animals were sacrificed 1 week after operation and membranes were prepared from the prostate, heart, brain, kidney, liver and lung for ET-1, ET-3 and angiotensin II (A-II, as a control) binding studies. No significant difference in A-II binding was observed between castrated and sham-operated animals. However, ET-1 and ET-3 binding to prostate and brain membranes were altered significantly. From saturation binding studies using ET-1 in the prostate, the K(d) and B(max) values increased from 0.043 nM and 0.094 pmol/mg respectively in sham-operated dogs to 0.104 nM and 0.311 pmol/mg respectively in castrated animals. These results indicate that surgical castration in dogs produces a change in the ET receptor density in the prostate and brain, and may have implications for the effect of hormone ablation therapy on ET receptor expression in prostate cancer patients.

Angiotensin II↗
PubMed1993

[Molecular biology of endothelins and endothelin receptors].

Endothelin (ET) was initially identified as a potent vasoconstrictor peptide with 21 amino-acid residues, produced by cultured porcine aortic endothelial cells. Cloning of the ET genes revealed the existence of three isopeptides, ET-1, ET-2 and ET-3, which are widely distributed in a variety of tissues and possess wide variety of pharmacological functions. Recently, two subtypes of ET receptor have been isolated by the expression cloning technique and the molecular characteristics of the receptors were elucidated. Subsequently, the structural organizations of the ET receptor genes have been investigated. This article discusses the structure, function and expression of ET ligands and receptors from the molecular biological aspect.

Amino Acid Sequence↗
PubMed1992

Distinct tissue distribution and cellular localization of two messenger ribonucleic acids encoding different subtypes of rat endothelin receptors.

Endothelins (ETs) are very potent vasoconstrictive peptides and have diverse functions in both vascular and nonvascular tissues. This investigation concerns the tissue distribution and cellular localization of rat mRNAs encoding two different subtypes of ET receptors (ETA and ETB). We isolated 46 cDNA clones from a rat lung cDNA library by hybridization with the bovine ETA cDNA. The characterization of these cDNA clones indicated that they represent either the ETA or ETB cDNA. In situ and blot hybridization analyses revealed that the rat ETA mRNA is predominantly expressed in vascular smooth muscle cells of a variety of tissues, bronchial smooth muscle cells, myocardium, and the pituitary gland. There is no significant expression of ETB mRNA in vascular smooth muscle cells, and ETA, thus, plays a primary role in ET-induced vascular contraction. ETB mRNA is more widely distributed in various cell types of many tissues. Its prominent expression is seen in glial cells throughout the brain regions, epithelial cells of the choroid plexus, ependymal cells lining the ventricle, myocardium, endothelial cells of glomeruli, and epithelial cells of the thin segments of Henle's loops. Our investigation demonstrates that the mRNAs for the two subtypes of rat ET receptors show specialized expression patterns of cell types in both brain and peripheral tissues.

Amino Acid Sequence↗
PubMed1994

Endothelin, endothelin receptors, and endothelin antagonists.

Endothelin is a peptide with potent biologic effects in vascular and nonvascular cells. Its effects are mediated by two receptors, ETA and ETB, and possibly also by a third receptor, ETC. In vascular smooth muscle cells, endothelin causes profound contraction and also has proliferative effects, mainly through activation of ETA but also through ETB receptors. Activation of endothelin receptors on vascular smooth muscle explains the profound vasoconstriction observed in isolated blood vessels as well as with infusion of the peptide in vivo. Endothelial cells can express ETB receptors linked to the formation of nitric oxide or prostacyclin. Activation of these receptors leads to the transient vasodilation observed with intravascular infusion of the peptide. In vascular smooth muscle, activation of endothelin receptors stimulates phospholipase C, with concomitant formation of inositol triphosphate and diacylglycerol. These events lead to the release of intracellular calcium and initiation of contraction. In addition, endothelin can activate voltage-operated calcium channels via Gi proteins, thereby increasing influx of extracellular calcium. The later phenomenon may explain the ability of calcium antagonists to inhibit endothelin-induced contractions. Normally, circulating endothelin levels, as well as production of the peptide in isolated blood vessels, are rather low due to the absence of stimuli and the presence of potent inhibitory mechanisms. Important stimulators of endothelin production are thrombin, angiotensin II, arginine vasopressin, and transforming growth factor-beta, as well as certain cytokines and physicochemical factors such as hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Two subtypes of endothelin receptors and endothelin peptides are expressed in differential cell types of the rat placenta: in vitro receptor autoradiographic and in situ hybridization studies.

We studied the localization of endothelin (ET) receptors and ET peptides in the rat placenta. In vitro receptor autoradiographic and in situ hybridization studies revealed the differential and cell-specific distribution of ET receptor subtypes, suggesting that each ET receptor plays a different role in the function of the placenta. The expression of the ETB receptor was concentrated to cytotrophoblasts and trophoblastic giant cells of the basal zone, in which fetal cells directly face maternal cells. The ETA receptor was confined to the decidual tissue and vascular wall. Both ET receptors coexisted in the labyrinth in an approximately 50:50 ratio. Prepro-ET-1 messenger RNA (mRNA) was detected in cytotrophoblasts and trophoblastic giant cells of the basal zone and endothelial cells of vessels, whereas ET-1-like immunoreactivity was present not only in trophoblasts and endothelial cells, but also in the decidual tissue and vascular wall. ET-3 mRNA was localized in migrating cells. We also found changes in the expression levels of ET receptors by means of a cold ligand saturation study. The number of specific [125I]ET-1-binding sites was increased in the basal zone and labyrinth with gestation, but not in the decidual tissue. The enhancement of ETA receptor, ETB receptor, and prepro-ET-1 mRNA levels was also supposed, based on data obtained by RT-PCR Southern hybridization. On the other hand, ET-3 mRNA levels were reduced with gestation. These findings support the idea that ETs, through interaction with ETA and ETB receptors, play an important role in the regulation of placental growth and fetoplacental circulation through autocrine and paracrine mechanisms.

Animals↗