Disease relevance of EDN3

• We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease [1].
• Novel EDNRB mutations have been detected in non-syndromic HD patients with heterozygous forms, and homozygous mutations of the EDNRB or the EDN3 genes have been reported in HD patients associated with type 2 Waardenburg syndrome [2].
• The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 +/- 1.6 pg/mL, 20.5 +/- 1.5 pg/mL, and 18.4 +/- 1.5 pg/mL, respectively) compared with controls (11.1 +/- 1.8 pg/mL, 11.3 +/- 1.5 pg/mL, and 10.1 +/- 1.7 pg/mL, respectively; P < .01) [3].
• ET-3, an ETB-selective agonist, also had no effect on prostate cancer growth [4].
• Moderate to strong staining was seen in 72% and 64% of carcinomas for ET-1 and ET-3, respectively [5].

Psychiatry related information on EDN3

• In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases [6].

High impact information on EDN3

• Here, we describe a mutation of the human gene for endothelin 3 (EDN3), homozygously present in a patient with a combined Waardenburg syndrome type 2 (WS2) and HSCR phenotype (Shah-Waardenburg syndrome) [7].
• Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome [8].
• This mutation prevents the proteolytic activation of big EDN3 by ECE-1 [1].
• Endothelin-1 and endothelin-3 are potent, long-acting vasoconstrictors, and endothelin-1 has selective potency as a renal vasoconstrictor [9].
• In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3 [10].

Chemical compound and disease context of EDN3

• AIMS: To study the serum and hepatic vein concentration of ET-1, ET-2, ET-3 and nitric oxide in patients with primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment [11].
• RESULTS: The results of a number of experiments are summarized, detailing the effects of hyperglycemia and the roles of factors such as protein kinase C activation, endothelin-1 and endothelin-3, angiotensin-II, and nitric oxide in the development of retinal blood flow abnormalities in diabetes [12].
• Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content [13].
• Statistical analysis of the data demonstrated minimal photobleaching of VBBO and a significant difference between the phototoxicity curves of ET3 and 2008 [14].

Biological context of EDN3

• However, details of EDN3 expression during embryogenesis are lacking, and consequently the cellular mechanism by which EDN3 regulates innervation of the terminal gut is unclear [15].
• However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype [16].
• Studies with human-mouse somatic cell hybrids have suggested that the gene EDN3 is localized on human chromosome 20 [17].
• Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation [18].
• Brachial artery infusion of endothelin-1 and endothelin-3 caused slow-onset dose-dependent forearm vasoconstriction [19].

Anatomical context of EDN3

• RESULTS: High levels of EDN3 mRNA expression were restricted to mesenchymal cells of the caecum before and after the arrival of neural crest cells [15].
• Endothelin 3 (EDN 3) and the endothelin receptor B (EDNRB) are involved in the development of neural crest and particularly of the melanocytes and the enteric nervous system [20].
• Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores [21].
• Competition binding experiments performed on HeLa cells transiently expressing pETc show that the apparent Ki values for ET-3 and ET-1 to displace [125I]ET-3 are 45.5 +/- 16 and 114 +/- 22 nM, respectively [21].
• Amoeboid microglial cells (AMC) which transiently exist in the corpus callosum in the postnatal rat brain expressed endothelins (ETs), specifically endothelin-1 (ET-1) and ET3 as revealed by real time RT-PCR [22].

Associations of EDN3 with chemical compounds

• Testosterone and Mullerian inhibiting substance had no deleterious effect on ENS precursor development, but adding EDN3 peptide to E11.5 male RetDN heterozygous mouse gut explants in organ culture significantly increased the rate of ENS precursor migration through the bowel [23].
• Furthermore, the differential ET-1 and ET-3 mRNA expression in LPS and OGD treatments may be due to different signaling pathways independently regulating the two isoforms [22].
• In both groups of segments, the response to ET-3 could be completely blocked by BQ-123 [24].
• Endothelin-1 and endothelin-3 regulate differently vasoconstrictor responses of smooth muscle of the porcine coronary artery [25].
• 7. To conclude we have demonstrated the presence of a phosphoramidon-sensitive ECE on the smooth muscle layer of the human umbilical vein which can convert big ET-1, big ET-2(1-37), big ET-2(1-38) and big ET-3 to their mature biologically active forms [26].

Physical interactions of EDN3

• Endothelin-2 and sarafotoxin S6B inhibited [125I]-PD151242 binding to renal tissue whereas ET-3 and sarafotoxin S6C were less effective [27].
• 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 [28].

Regulatory relationships of EDN3

• ET-3 also stimulated growth (36 +/- 3.8%) but was less potent than ET-1 (threshold, 10(-9) M; maximal, 10(-7) M) [29].
• Neither ET-1 nor ET-3 induces secretion of CXCL8 in primary human melanocytes; thus, this response may be specific for melanocytic cells that have undergone malignant transformation [30].
• We found that the vasoactive peptides endothelin (ET)-1 and ET-3 stimulated the synthesis of VEGF protein 3-4-fold in cultured human vascular smooth muscle cells, comparable in magnitude to hypoxia [31].
• Consistent with such a role, the proportion of Sox10-expressing progenitors in the total population of enteric neural crest cells is reduced in the gut of endothelin 3-deficient embryos [32].
• In addition, ET-3 (1 to 100 nM) stimulated ADM release only from ET(A)/ET(B) isolates, implicating the ET(B) receptor in this response [33].

Other interactions of EDN3

• Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min) [19].
• EDN1, EDN2, and EDN3 were mapped to 6p23-p24, 1p34, and 20q13.2-q13.3, respectively [34].
• WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations [35].
• METHODS: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls [36].
• In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM [37].

Analytical, diagnostic and therapeutic context of EDN3

• Reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of EDN3 and EDNRB mRNA [38].
• Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays [3].
• The conversion to ET-3 was confirmed with sandwich EIA by monoclonal antibodies, the elution profile of HPLC, and intracellular calcium mobilization in CHO-K1 cells expressing recombinant human ET(B) receptors [39].
• 1. Using front-surface fluorometry of fura-2 and medial strips of the porcine coronary artery, we investigated mechanisms by which endothelin-1 (ET-1) and ET-3 function as vasoconstrictors [25].
• Plasma immunoreactive endothelin-3 (ir-ET-3) concentrations were measured by a sandwich-enzyme immunoassay (sandwich-EIA) for endothelin-3 (ET-3) [40].

References