Disease relevance of Edn1

• Interspecific backcross mapping located Edn1 in the central region of chromosomal 13, where a mouse mutation, congenital hydrocephalus (ch), is also mapped [1].
• In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed [2].
• Under pathological conditions such as ischemia (I), subarachnoid hemorrhage, and Alzheimer's disease, astrocytes show a large increase in endothelin (ET) -like immunoreactivity [3].
• Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells [4].
• Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice [5].

Psychiatry related information on Edn1

• The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain [6].
• ET-1 and ET-3 produced central depressive effects demonstrated by depressive behavior signs, decrease of the spontaneous and amphetamine-stimulated motor activity, and prolongation of the hexobarbital-induced narcosis [7].
• In addition, since ET-antagonists lowered per se the control reaction time of the mice when administered alone to the PAG area, we would suggest that endogenous ET-1 acting within the PAG area contributes to the suppression of pain [8].

High impact information on Edn1

• Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons [9].
• These findings indicate that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages [9].
• Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans [9].
• However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families [10].
• The temporal requirement for endothelin receptor-B signalling during neural crest development [11].

Chemical compound and disease context of Edn1

• To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells [4].
• Endothelin-1 (ET-1) is a potent vasoconstrictor peptide whose levels are elevated in numerous disease states, including obesity and diabetes [12].
• These data suggest that ET and ET receptor gene transcription is upregulated in the renal tissues of NZB/W F1 mice and that the beneficial treatment of lupus nephritis with MPSL is accompanied by a reduction in the elevated concentrations of ET-1, ET receptors, TGF-beta and TNF-alpha mRNAs [13].
• Investigation into the potential anti-inflammatory effects of endothelin antagonists in a murine model of experimental monosodium urate peritonitis [14].
• In the presence of 10 microM GTP gamma S, ET-1 induces the formation of inositol phosphates with an EC50 value of 2.5 nM for C6 glioma cells and 1.6 nM for NIH 3T3 cells [15].

Biological context of Edn1

• Edn1 comprises five exons, and the open reading frame encodes the 202-amino-acid preproET-1 [1].
• Neither compensation by redundant expression of other ET isoforms nor upregulation of ET receptors could explain the elevated blood pressure in Edn1+/- heterozygous mice [16].
• This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis [2].
• The present study suggests that astrocytes without ET-1 are more vulnerable to H and H/I injuries and that the up-regulation of astrocytic ET-1 is essential for the survival of astrocytes [3].
• Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization [17].

Anatomical context of Edn1

• Tissue-mosaic studies indicate that, among these tissues, a crucial source of Edn1 is the surface ectoderm [18].
• The highest expression of Edn1 mRNA is detected in the lung in adult mice, whereas Edn1 is predominantly expressed in the epithelium and mesenchyme of the pharyngeal arches and in the endothelium of the large arteries [1].
• Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice [19].
• Endothelin-1 protects astrocytes from hypoxic/ischemic injury [3].
• In this study, we assessed the potential role of Src kinase in ET-1 signaling to glucose transport in 3T3-L1 adipocytes [20].

Associations of Edn1 with chemical compounds

• IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin [21].
• Consistent with this finding, IFN-gamma and ET-1 induced dose- and time-dependent mechanical hypernociception that was inhibited by BQ123 or indomethacin but not BQ788 (an ET(B) receptor antagonist) [21].
• Under H and H/I conditions, ET-1 peptide and mRNA were up-regulated in wild-type astrocytes, and the astrocytes without ET-1 died faster than the wild-type astrocytes, as indicated by greater efflux of lactate dehydrogenase [3].
• Overexpression or microinjection of a dominant negative mutant (K298M) of Src kinase also inhibited ET-1-induced Galpha(q/11) tyrosine phosphorylation and GLUT4 translocation [20].
• In the present study, we have investigated the ET-1 gene in vivo as a potential direct aldosterone-regulated target gene in the kidney and colon [22].

Physical interactions of Edn1

• Targeted deletion of the G-protein-coupled endothelin receptors ET(A) and ET(B) was shown to result in characteristic developmental defects of derivatives of cephalic and cardiac neural crest and of neural crest-derived melanocytes and enteric neurons, respectively [23].
• This is the first time that a peptide structurally unrelated to ET1 or VIC is shown to block the binding and mitogenic effects of peptides of the endothelin family [24].
• The endothelin receptor involved in phospholipase C stimulation in C6 cells seems to correspond to a 74 kDa protein which binds ET-1 but not ET-3 [15].
• The expression of endothelin-1 and its binding sites in mouse skin increased after ultraviolet B irradiation or local injection of tumor necrosis factor alpha [25].
• Therefore, the thrombin, LPA, thromboxane A2, and endothelin receptors may be able to couple to Galpha12/13 [26].

Enzymatic interactions of Edn1

• Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin [27].

Regulatory relationships of Edn1

• The effects of ET-1 were blocked by a specific ETA (BQ123, pA(2) 7.4) but not by a specific ETB receptor antagonist (BQ788) [28].
• Endothelin-1 inhibits TNF alpha-induced iNOS expression in 3T3-F442A adipocytes [28].
• The ET-1-induced response in Cav-1(-/-) cells was mediated by the ET(B) receptor, as shown using the ET(B) receptor antagonist BQ-788 and the ET(A) receptor antagonist BQ-123 [29].
• Endothelin-1 inhibits adiponectin secretion through a phosphatidylinositol 4,5-bisphosphate/actin-dependent mechanism [30].
• IFN-gamma induced the production of ET-1 and the expression of its mRNA precursor (preproET-1, PPET-1) [21].
• Endothelin-1 stimulated Akt activity by 0.16 +/- 0.02 arbitrary units as measured by fluorescence resonance energy transfer (p < 0.001; n = 5) and increased phosphorylation of Akt at Ser473 by 56 +/- 11% (p < 0.002; n = 7) [31].

Other interactions of Edn1

• Collectively, our results indicate that Edn1 from the pharyngeal ectoderm signals through Ednra proteins to direct early dorsoventral patterning of the skeletogenic neural crest [18].
• 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype [28].
• Gene expression of vasoactive intestinal contractor/endothelin-2 in ovary, uterus and embryo: comprehensive gene expression profiles of the endothelin ligand-receptor system revealed by semi-quantitative reverse transcription-polymerase chain reaction analysis in adult mouse tissues and during late embryonic development [32].
• 5. Differentiated 3T3-F442A adipocytes did not release ET-1 with or without exposure to TNFalpha, although the mRNA for preproET-1 was detected in both pre- and differentiated adipocytes [28].
• Therefore, Cav-1 ablation increased the ET-1-induced Ca(2+) response in SMCs by altering the type and expression level of the ET receptor (i.e., receptor isoform switching) [29].

Analytical, diagnostic and therapeutic context of Edn1

• Microinjection of beta-arrestin 1 antibody inhibited ET-1- but not insulin-stimulated GLUT4 translocation [20].
• The mRNA expressions for ET-1 and endothelin (ET) receptors were quantified by real-time PCR [33].
• The Ca(2+) response was examined in the presence of ET-1 and assessed by confocal microscopy with the Ca(2+)-sensitive fluorescent probe fluo 3 [29].
• No dose of BQ-123 blocked ET-1-induced constriction, whereas pretreatment with each dose of BQ-788 significantly inhibited ET-1-induced responses [34].
• We now sought to determine, in an animal model of angiogenesis, if inhibiting the effect of ET-1 on endothelial cells (ECs) would reverse the CyA-mediated endothelial injury in an animal model of angiogenesis [35].

References