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Stuart H Orkin - One of the best experts on this subject based on the ideXlab platform.
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downregulation of Endothelin receptor b contributes to defective b cell lymphopoiesis in trisomy 21 pluripotent stem cells
Scientific Reports, 2018Co-Authors: Glenn A Maclean, Jennifer Mceldoon, Jialiang Huang, Jeremy Allred, Matthew C Canver, Stuart H OrkinAbstract:Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding Endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for Endothelin signaling in regulation of B cell development has been identified.
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downregulation of Endothelin receptor b contributes to defective b cell lymphopoiesis in trisomy 21 pluripotent stem cells
Scientific Reports, 2018Co-Authors: Glenn A Maclean, Jennifer Mceldoon, Jialiang Huang, Jeremy Allred, Matthew C Canver, Stuart H OrkinAbstract:Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding Endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for Endothelin signaling in regulation of B cell development has been identified.
Nicola J Smith - One of the best experts on this subject based on the ideXlab platform.
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drug discovery opportunities at the Endothelin b receptor related orphan g protein coupled receptors gpr37 and gpr37l1
Frontiers in Pharmacology, 2015Co-Authors: Nicola J SmithAbstract:Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the Endothelin B receptor-like proteins, GPR37 [ET(B)R-LP, Pael-R] and GPR37L1 [ET(B)R-LP-2]. Originally identified through searches for homologs of Endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind Endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson's disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored.
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Drug discovery opportunities at the Endothelin B receptor-related orphan G protein-coupled receptors, GPR37 and GPR37L1
Frontiers Media S.A., 2015Co-Authors: Nicola J SmithAbstract:Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the Endothelin B receptor-like proteins, GPR37 (ET(B)R-LP, Pael-R) and GPR37L1 (ET(B)R-LP-2). Originally identified through searches for homologues of Endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind Endothelins or related peptides. Instead, GPR37 was proposed to be activated by Head Activator and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson’s disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored
Masashi Yanagisawa - One of the best experts on this subject based on the ideXlab platform.
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Endothelin b receptor is not required but necessary for finite regulation of ovulation
Life Sciences, 2012Co-Authors: Jongki Cho, Heyyoung Kim, Dong Wook Kang, Masashi YanagisawaAbstract:Aims In the ovary, Endothelins regulate a variety of ovarian functions that include but not limited to folliculogenesis, steroidogenesis, oocyte maturation, ovulation and corpus luteum (CL) function. Two cognate receptors, EDNRA and EDNRB are constitutively expressed in the ovary, and mediate the regulatory Endothelin actions. However, the physiological significance of the presence of the two receptors that often elicit opposite responses upon activation by an Endothelin is yet to be determined. This study was proposed to test the hypothesis that both receptors are present in the ovary to lend an Endothelin a finite regulation of ovulation.
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Endothelins are vascular derived axonal guidance cues for developing sympathetic neurons
Nature, 2008Co-Authors: Takako Makita, Henry M Sucov, Cheryl E Gariepy, Masashi Yanagisawa, David D GintyAbstract:During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the Endothelin family member Edn3 (ref. 1), acting through the Endothelin receptor EdnrA (refs 2, 3), directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived Endothelins, and have broad implications for Endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.
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dual genetic pathways of Endothelin mediated intercellular signaling revealed by targeted disruption of Endothelin converting enzyme 1 gene
Development, 1998Co-Authors: Hiromi Yanagisawa, James A Richardson, Masashi Yanagisawa, Raj P Kapur, S C Williams, David E Clouthier, D De WitAbstract:Recent gene targeting studies have revealed unexpected roles for Endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big Endothelin-1 to Endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple Endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1-/- term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and Endothelin A receptor (ETA)-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1-/- embryos, reproducing the developmental phenotype seen in ET-3-/- and Endothelin B receptor (ETB)-/- mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1-/- embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce sufficient mature Endothelin at the locations crucial for normal embryonic development. These findings reveal that ECE-1 is a bona fide activating protease for both big ET-1 and big ET-3 in vivo, and that the cell-cell communication pathways represented by the ET-1/ECE-1/ETA axis and the ET-3/ECE-1/ETB axis are each involved in the development of distinct subsets of neural crest cell lineages. Mutations in ECE-1 may cause developmental defects in humans, such as Hirschsprung disease, velocardiofacial syndrome and related neurocristopathies.
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targeted and natural piebald lethal mutations of Endothelin b receptor gene produce megacolon associated with spotted coat color in mice
Cell, 1994Co-Authors: Kiminori Hosoda, Amy Greenstein Baynash, Adel Giaid, James A Richardson, Robert E Hammer, Jason C Cheung, Masashi YanagisawaAbstract:Endothelins act on two subtypes of G protein-coupled receptors, termed Endothelin-A and Endothelin-B receptors. We report a targeted disruption of the mouse Endothelin-B receptor (EDNRB) gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans, and other mammalian species. Piebald-lethal (sl) mice exhibit a recessive phenotype identical to that of the EDNRB knockout mice. In crossbreeding studies, the two mutations show no complementation. Southern blotting revealed a deletion encompassing the entire EDNRB gene in the sl chromosome. A milder allele, piebald (s), which produces coat color spotting only, expresses low levels of structurally intact EDNRB mRNA and protein. These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes. We postulate that defects in the human EDNRB gene cause a hereditary form of Hirschsprung's disease that has recently been mapped to human chromosome 13, in which EDNRB is located.
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Endothelins : vasoconstrictor effects and localization in canine cerebral arteries
British journal of pharmacology, 1991Co-Authors: Akira Saito, Tomoh Masaki, Masashi Yanagisawa, Sadao Kimura, Reiko Shiba, Koei Yamada, Tatsuo Mima, Taku Shigeno, Katsutoshi GotoAbstract:1. The vascular effects of Endothelin and localization of Endothelin-like immunoreactivity were characterized in isolated cerebral arteries of dogs. 2. Endothelin-like immunoreactivity was detected in a few populations of endothelial cells of dog basilar artery. 3. Endothelin-1, Endothelin-2 and Endothelin-3 contracted isolated ring preparations of cerebral arteries in a dose-dependent manner independently of the presence of endothelium. The ED50 values (and 95% confidence intervals) for the contraction were 411 pM (242-697 pM) and 478 pM (295-776 pM) for Endothelin-1 and Endothelin-2, respectively. Endothelin-3 induced vascular contraction at a higher concentration (ED50 = 26.5 nM, 95% confidence interval = 15.7-45.7 nM). 4. The increases in tone induced by Endothelin-1 and Endothelin-2 did not return to the resting level after repeated washings, while a rinse with Krebs solution reversed the vasoconstrictor response to Endothelin-3. The Endothelins did not cause any vasodilator response in arteries precontracted with uridine 5'-triphosphate even in the presence of intact endothelial cells. 5. NiCl2 (1 mM) attenuated the contractions induced by Endothelin-3 (10-300 nM) and those to relatively low doses (1 nM) but not higher doses (10-100 nM) of Endothelin-1 and Endothelin-2. The contractions in response to Endothelin-1, Endothelin-2 and Endothelin-3 were greatly attenuated in Ca(2+)-free solutions although high concentrations of Endothelin-1 and Endothelin-2 still evoked contractions. 6. These results suggest that the vasoconstriction induced by Endothelin-3 and lower doses of Endothelin-1 and Endothelin-2, largely depends on the influx of Ca2+ ions. The apparent insensitivity to Ni2+ shows that additional distinct mechanisms also operate in the vasconstrictor responses to high concentrations of Endothelin-1 and Endothelin-2. 7. The presence of Endothelin-like immunoreactivity in endothelial cells suggests that Endothelin is a potential endogenous spasmogen.
Anthony P Davenport - One of the best experts on this subject based on the ideXlab platform.
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international union of pharmacology xxix update on Endothelin receptor nomenclature
Pharmacological Reviews, 2002Co-Authors: Anthony P DavenportAbstract:In mammals, the Endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, Endothelins mediate their actions via only two receptor types that have been cloned and classified as the ETA and ETBreceptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of Endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of Endothelin. A selective ETA receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[d-Asp-l-Pro-d-Val-l-Leu-d-Trp-]; FR139317, N - [(hexahydro-1-azepinyl)carbonyl]l-Leu(1-Me)d-Trp-3 (2-pyridyl)-d-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala11,15]Ac-ET-1(6–21)), and IRL1620 [Suc-(Glu9, Ala11,15)-ET-1(8–21)] are widely used synthetic ETB receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ETB antagonists have also been developed. They are generally less potent than ETA antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ETB receptor. Radioligands highly selective for either ETA(125I-PD151242, 125I-PD164333, and3H-BQ123) or ETB receptors (125I-BQ3020 and 125I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals.
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effects of phosphoramidon and pepstatin a on the secretion of Endothelin 1 and big Endothelin 1 by human umbilical vein endothelial cells measurement by two site enzyme linked immunosorbent assays
Clinical Science, 1994Co-Authors: Christopher Plumpton, S Kalinka, R C Martin, J K Horton, Anthony P DavenportAbstract:1. Two-site enzyme-linked immunosorbent assays have been developed for the rapid, sensitive and non-isotopic measurement of Endothelin-1 and big Endothelin-1. The sensitivities of detection were 0.5 and 0.3 fmol/well, with ED50 values of 13 and 12 fmol/well for the Endothelin-1 and big Endothelin-1 assays, respectively. Each assay is highly selective for its corresponding antigen. The ET-1 assay showed no detectable cross-reactivity with ET-1-(1-20), indicating that the assay only recognizes the 21-amino acid biologically active peptide. 2. The two assays were used to measure the effects of two classes of protease inhibitor on the basal release of enothelin-1 and big Endothelin-1 from cultured first-passage human umbilical vein endothelial cells. 3. The secretion of both peptides was time-dependent over 12 h. The metalloprotease inhibitor phosphoramidon (1 x 10(-4) mol/l) significantly reduced the amount of Endothelin-1 secreted into the medium (P < 0.05), with a concomitant increase in the secreted levels of big Endothelin-1 (P < 0.01). The aspartyl protease inhibitor, pepstatin A, also caused a significant decrease in the secretion of Endothelin (P < 0.05). However, unlike phosphoramidon, there was no increase in the levels of big ET-1 compared with the controls. At these concentrations, neither inhibitor affected the viability of the cells as indicated by Trypan Blue exclusion. 4. The two assays permit the direct measurement of Endothelin-1 and its precursor, and will be of use in the elucidation of the putative human Endothelin-converting enzyme(s).(ABSTRACT TRUNCATED AT 250 WORDS)
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anatomical localization and pharmacological activity of mature Endothelins and their precursors in human vascular tissue
Journal of Hypertension, 1992Co-Authors: Paisley G Howard, C Plumpton, Anthony P DavenportAbstract:OBJECTIVES We developed four selective rabbit antisera in order to compare the distribution of immunoreactive mature Endothelins and their precursors, proEndothelin-1, proEndothelin-2 and proEndothelin-3, in the endothelium from human vascular tissue. Our second aim was to use in vitro pharmacological assays to test the vasoconstrictor actions of the mature Endothelin and proEndothelin peptides. METHODS The antisera were shown to be selective by enzyme-linked immunosorbent assays. With these antisera, we detected immunoreactivity in serial cryostat sections from saphenous and mesenteric veins, and mesenteric and internal mammary arteries, using a peroxidase-antiperoxidase technique. In pharmacological experiments, segments of human coronary and mesenteric arteries were exposed to cumulative (0.06-60 nmol/l) concentrations of the Endothelins and their precursors. RESULTS Antisera directed against mature Endothelin stained the cytoplasm of endothelial cells in all vessels tested. Immunoreactive proEndothelin-1 and proEndothelin-2 were also detected, but not proEndothelin-3. Endothelin-1 and Endothelin-2 were strongly vasoactive, with similar molar potencies, and caused a dose-related increase in contractile force in human coronary arteries (0.06-60 nmol/l). However, proEndothelin-1 and proEndothelin-2 were 100-fold and 1000-fold less vasoactive than their respective mature peptides. No contractile effect was seen with proEndothelin-3 or Endothelin-3 at the concentrations tested in human coronary arteries, and similar results were obtained with human mesenteric arteries. CONCLUSIONS These results suggest that proEndothelin-1 and proEndothelin-2 must be converted to their corresponding mature peptides to produce vasoconstrictor activity in human vessels. Immunoreactive mature Endothelin is widely distributed in human vascular endothelial cells and, if released, may produce Endothelin-mediated vasoconstriction.
Glenn A Maclean - One of the best experts on this subject based on the ideXlab platform.
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downregulation of Endothelin receptor b contributes to defective b cell lymphopoiesis in trisomy 21 pluripotent stem cells
Scientific Reports, 2018Co-Authors: Glenn A Maclean, Jennifer Mceldoon, Jialiang Huang, Jeremy Allred, Matthew C Canver, Stuart H OrkinAbstract:Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding Endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for Endothelin signaling in regulation of B cell development has been identified.
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downregulation of Endothelin receptor b contributes to defective b cell lymphopoiesis in trisomy 21 pluripotent stem cells
Scientific Reports, 2018Co-Authors: Glenn A Maclean, Jennifer Mceldoon, Jialiang Huang, Jeremy Allred, Matthew C Canver, Stuart H OrkinAbstract:Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding Endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for Endothelin signaling in regulation of B cell development has been identified.