Disease relevance of Edn3

• The requirement for SOX10 and endothelin-3/EDNRB signalling pathway during enteric nervous system (ENS) and melanocyte development, as well as their alterations in Waardenburg-Hirschsprung disease (hypopigmentation, deafness and absence of enteric ganglia) are well established [1].
• All three peptides potentiated the second phase (10-30 min after injection) of formalin-induced nociception (at 3-30, 1-30, and 10-30 pmol/paw for ET-1, ET-3, and SRTX-c, respectively), whereas only ET-1 (10 or 30 pmol/paw) effectively enhanced edema caused by formalin (30 min after injection) [2].
• Moreover, mutations in the human ET-3 and ET-B receptor genes have been identified in patients with Hirschsprung disease [3].
• In contrast, mice lacking the ET-3/ET-B receptor-mediated signalling have defects in enteric neurons and melanocytes derived from trunk/vagal neural crest, resulting in megacolon and coat color spotting [3].
• Exogenous ET-1 and ET-3 are causally associated with experimental gastric ulcers [4].

Psychiatry related information on Edn3

• 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 [5].

High impact information on Edn3

• The lethal-spotted mouse which has pigment abnormalities, but also colonic aganglionosis, carries a mutation in the gene coding for endothelin 3 (Edn3), the ligand for the receptor protein encoded by EDNRB [6].
• A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome) [6].
• Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons [7].
• The targeted gene inactivation of endothelins-1 and -3 (ET-1 and ET-3) and of one of their receptors, ETB, in the mouse causes severe defects in the embryonic development [8].
• Genetic data in the mouse have shown that endothelin 3 (ET3) and its receptor B (ETRB) are essential for the development of two neural crest (NC) derivatives, the melanocytes and the enteric nervous system [9].

Biological context of Edn3

• Consistent with this, neither Ednrb nor Edn3 mRNA was detected in 3/3 tested immortal lines of mouse melanoblasts and 5/5 lines of melanocytes, of various genotypes [10].
• Intravenous ET-1, ET-2, and ET-3 increased lung resistance similarly and equipotently, whereas S6c elicited a greater degree of bronchoconstriction [11].
• The data from competitive binding experiments with [125I]ET-1 and unlabeled ET-1, ET-3 and receptor subtype selective ligands yielded a single class of high affinity binding sites with ETA receptor subtype characteristics [12].
• RESULTS: ET-1, ET-3 and S6c (1-100 microM, 30 microliters) induced dose-dependent vasoconstriction of the portal venules, the sinusoids and the central venules [13].
• Immunoblot analysis with an anti-phosphotyrosine antibody showed that ET-3 (1 nM) increased tyrosine phosphorylation of 120 Kda and 70 Kda astrocytic proteins [14].

Anatomical context of Edn3

• Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development [1].
• Numbers of early (migrating) embryonic melanoblasts are low in Ednrb(ls) mutant mice, while added Edn3 appears to promote the growth of melanocyte precursors in neural crest cultures [10].
• Endothelin-3 attenuates the cyclic GMP responses to C-type natriuretic peptide in cultured mouse astrocytes [15].
• The results support the premise that ET-3 and CNP interact within the central nervous system [15].
• Development of melanocyte progenitors in murine Steel mutant neural crest explants cultured with stem cell factor, endothelin-3, or TPA [16].

Associations of Edn3 with chemical compounds

• Staurosporine, Ro 31-8220, calcium-free medium, nifedipine, verapamil, lanthanum, thapsigargin, BAPTA, W7, calmidazolium, U-73122, neomycin, quinacrine, wortmannin, herbimycin-A, okadaic acid, and sodium orthovanadate failed to block the effect of ET-3 [15].
• Cycloheximide (100 microM), however, partially but significantly reversed the inhibitory effect of ET-3 on CNP-induced cGMP from 48.2 to 73.3% of the control value [15].
• Neurons and glia developed only in cultures of crest-derived cells, and did so even when endothelin-3 was absent and BQ 788 was present [17].
• Endothelin-3 failed to stimulate the incorporation of [3H]thymidine or bromodeoxyuridine [17].
• 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 [18].

Regulatory relationships of Edn3

• On the other hand, it has been demonstrated that the addition of endothelin 3 (ET-3) or TPA to neural crest cell cultures can induce melanocyte differentiation without addition of extrinsic SCF [16].
• Responses to endothelin-3 were progressively inhibited by the selective endothelin ETA receptor antagonist BQ-123 (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]) (10, 30 and 100 nM) [19].

Other interactions of Edn3

• Only Edn3 and Gnas did not recombine with the ls mutation [20].
• The first phase of nociception (0-5 min after injection) was significantly potentiated by simultaneous injection of either ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selective ET3 receptor agonist sarafotoxin S6c (SRTX-c; up to 30 pmol/paw) [2].
• BQ-123 (a selective ETA receptor antagonist) inhibited the constrictive effects of ET-3 (not of ET-1) on the portal venules and central venules, whereas it had no inhibitory effect on the sinusoids [13].
• Addition of the Kit ligand Mgf or endothelin 3 or a combination of these factors all rapidly increased the number of Dct-positive cells [21].
• Most striking was the marked elevation of c-fos steady-state mRNA and protein by ET-1, as compared with ET-3 [22].

Analytical, diagnostic and therapeutic context of Edn3

• Baroreflex sensitivity, which was calculated as the slope of the relationship between systolic BP and RR interval on an ECG, was also similar in ET-3 (-/-) mice (0.84+/-0.20 ms/mmHg) and wild-type mice (1.07+/-0.38 ms/mmHg) [23].
• To investigate the possible involvement of ET-3 in central ventilatory control, we measured ventilation in mutant mice deficient in ET-3 by whole body plethysmography [24].
• This article describes the development of an organ culture model using embryonic murine gut to determine how endothelin-3 regulates development of the enteric nervous system [25].
• Using quantitative real-time polymerase chain reaction (PCR) we demonstrated reduced levels of endothelin converting enzyme-1 and endothelin-3 mRNA in the male mouse bowel at the time that ENS precursors migrate into the colon [26].
• Characterization by reversed phase HPLC revealed, however, that a major portion of the neostriatal ET-3-like immunoreactivity was not identical to ET-3 [27].

References