Disease relevance of EDNRB

• Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease [1].
• We found somatic methylation of CpG island sequences in EDNRB in 5 of 5 human prostate cancer cell lines, 15 of 21 primary prostate cancer tissues, and 8 of 14 prostate cancer metastases (70% of samples overall) [2].
• In 16 of 17 melanoma cell lines, however, the expression of EDNRB mRNA was strongly downregulated [3].
• To further investigate the involvement of other genes, mutation analysis of the endothelin-B receptor (EDNRB) gene was performed in 52 unrelated sporadic HSCR patients, including 38 non-syndromic and 14 patients with HSCR and Down's syndrome [4].
• RESULTS: EDNRB methylation was found in 40 of 48 of the adenocarcinomas [5].

Psychiatry related information on EDNRB

• Hirschsprung disease (distal intestinal aganglionosis, HSCR) is a multigenic disorder with incomplete penetrance, variable expressivity, and a strong male gender bias [6].

High impact information on EDNRB

• We identified in HSCR patients a G-->T missense mutation in EDNRB exon 4 that substitutes the highly conserved Trp-276 residue in the fifth transmembrane helix of the G protein-coupled receptor with a Cys residue (W276C) [7].
• We recently mapped a recessive susceptibility locus (HSCR2) to human chromosome 13q22, which we now demonstrate to be the endothelin-B receptor gene (EDNRB) [7].
• The cells also displayed ET receptor mRNAs and high-affinity binding sites for ET-1, mostly of the ETB type [8].
• In conclusion, ET-1 inhibits proliferation of activated HSC via ETB receptors, through a prostaglandin/cAMP pathway that leads to inhibition of both extracellular signal-regulated kinase and c-Jun kinase activities [9].
• Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a positive feedback loop that would amplify the growth inhibitory response [9].

Chemical compound and disease context of EDNRB

• We examined this regulatory region of the ETB receptor gene (EDNRB) to determine whether hypermethylation of cytidine nucleotides accompanies decreased ETB expression in human prostate cancer [2].
• Accordingly, we wished to investigate endothelin-1, endothelin-A (ETA) receptor, and endothelin-B (ETB) receptor gene expression, localization, and properties in aldosterone-producing adenomas and in the normal human adrenal cortex [10].
• Twelve beagles (pulmonary hypertension, n = 6; control group, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (an ETA receptor antagonist), RES-701-1 (an ETB receptor antagonist), nitroglycerin and prostaglandin E1 [11].
• The first dual ETA/ETB receptor blocker, bosentan, has already been approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension (PAH) [12].
• METHODS: Two PSA secreting prostate cancer cell lines (LAPC4 and LNCaP) were treated with atrasentan and an ETB receptor antagonist (A192621) in varying concentrations (10(-6)-10(-10) M) and PSA levels were measured in the culture media [13].

Biological context of EDNRB

• We reported previously that the avian EDNRB gene is expressed in the neural fold before crest cell migration and later on in all the neural crest derivatives except, at any developmental stage, in the melanocytic lineage [14].
• In addition, a missense mutation in the endothelin-B receptor (EDNRB) gene on chromosome 13q22 was found in an inbred Mennonite kindred affected by HSCR and associated abnormalities, demonstrating the involvement of EDNRB in HSCR pathogenesis [15].
• We have identified two novel EDNRB mutations: a missense mutation in a sporadic case, S305N, which leads to a change of a serine to an asparagine, disrupting a putative phosphorylation site; and a single nucleotide deletion in a familial case, N378I, resulting in a truncated protein [15].
• These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features [1].
• It is unlikely that the EDNRB variant contributes to the phenotype [16].

Anatomical context of EDNRB

• Its expression pattern differs from that of the "classical" avian EDNRB because it is strongly expressed in melanoblasts and melanocytes [14].
• HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system [17].
• During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts [18].
• In the EDNRB locus, two mutations were observed; a nonsense mutation of Trp to stop at codon 275, and a T insertion at nucleotide 878, in patients with aganglionosis confined to the rectosigmoid colon, and the descending colon, respectively [19].
• The expression of EDNRB became detectable in HeLa cells after treatment with a demethylating reagent, 5'-aza-2'-deoxycytidine, which was further enhanced in the transformed cells over-expressing SOX10 [20].

Associations of EDNRB with chemical compounds

• Mutation analysis revealed a heterozygous T>C missense mutation in exon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90 residue in the extracellular domain of the G protein-coupled receptor with an arginine residue (C90R) [21].
• The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin [22].
• Moreover, the ETB receptor agonist sarafotoxin S6c induced contraction in vessels preincubated with FR139317 [22].
• CONCLUSIONS: Vascular smooth muscle cells of human IMA, IMV, and PCA contain both ETA and ETB receptors, whereas the endothelium of IMA and PCA does not express functional ETB receptors linked to nitric oxide and/or prostacyclin production [22].
• CONCLUSIONS: Selective ETB receptor agonists cause constriction of forearm resistance and hand capacitance vessels in vivo in humans, suggesting that both ETA and ETB receptors mediate vasoconstriction [23].

Physical interactions of EDNRB

• Taken together, these data support the hypothesis that Asp126 and Asp133 flanking Tyr129 in TM2 of the ETA receptor play a role in defining ETA subtype-selective ligand binding but Asp147 and Asp154 that flank the His150 in TM2 of the ETB receptor do not [24].
• We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis [25].
• The 5' region for the endothelin receptor B (EDNRB) gene is a complex CpG island giving rise to four individual transcripts initiating within the island [26].
• In conclusion, using two cell systems, we demonstrated that the ETB receptor is functionally coupled to NOS and coordinates the generation of NO via a tyrosine kinase-dependent and a calcium/calmodulin-dependent pathway [27].

Regulatory relationships of EDNRB

• We also demonstrated that each receptor subtype expressed on the same cell could work independently, i.e. for hETA to activate G alpha s and for hETB to activate G alpha i, resulting in dose-dependent dual effects of ET-1 on cAMP formation [28].
• Here, we provide evidence that SOX10 regulates the expression of EDNRB gene in human melanocyte-lineage cells, as judged by RNA interference and chromatin immunoprecipitation analyses [20].
• Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression [29].
• Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors [30].
• The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure [31].

Other interactions of EDNRB

• Results showed that the ET-1, ETA and ETB mRNA can be detected by RT-PCR in all adrenal cortices as well as in the APA [32].
• WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations [33].
• Mutations in EDNRB, EDN3, and GDNF were found in four, two, and none of the patients, respectively [17].
• In contrast, E189X and Q377X proteins, each of which lacks its C-terminal portion, activated the EDNRB promoter, whereas no activation was detected with the SOX10 proteins mutated at the DNA-binding domain, 482ins6 and S135T [34].
• Here, we investigated the functions of SOX10 mutant proteins using the target promoters, EDNRB and MITF [34].

Analytical, diagnostic and therapeutic context of EDNRB

• Using RT-PCR and rapid amplification of 5' cDNA ends (5' RACE), we have cloned three previously unrecognized endothelin B receptor (EDNRB) transcripts from a human melanoma cell line [35].
• Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 of EDN-3 gene were amplified by polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP) [36].
• ETB receptor mRNA was detected by Northern blot analysis in IMA and aortic smooth muscle cells [22].
• The predominance of ETB binding on human benign prostatic epithelial tissue is not present in metastatic prostate cancer by autoradiography [37].
• In the lungs of newborns with CDH, immunohistochemistry of both ETA and ETB receptors demonstrated over-expression in the thickened media of pulmonary arteries [38].

References