Endothelin receptor type B explained

Endothelin receptor type B, (ET-B) is a protein that in humans is encoded by the EDNRB gene.^[1]

Function

Endothelin receptor type B is a G protein-coupled receptor which activates a phosphatidylinositol-calcium second messenger system. Its ligand, endothelin, consists of a family of three potent vasoactive peptides: ET₁, ET₂, and ET₃. A splice variant, named SVR, has been described; the sequence of the ETB-SVR receptor is identical to ETRB except for the intracellular C-terminal domain. While both splice variants bind ET₁, they exhibit different responses upon binding which suggests that they may be functionally distinct.^[2]

Regulation

In melanocytic cells the EDNRB gene is regulated by the microphthalmia-associated transcription factor. Mutations in either gene are links to Waardenburg syndrome.^{[3] [4]}

Clinical significance

The multigenic disorder, Hirschsprung disease type 2, is due to mutation in endothelin receptor type B gene.^[5]

Animals

In horses, a mutation in the middle of the EDNRB gene, Ile118Lys, when homozygous, causes Lethal White Syndrome.^[6] In this mutation, a mismatch in the DNA replication causes lysine to be made instead of isoleucine.^[6] The resulting EDNRB protein is unable to fulfill its role in the development of the embryo, limiting the migration of the melanocyte and enteric neuron precursors. A single copy of the EDNRB mutation, the heterozygous state, produces an identifiable and completely benign spotted coat color called frame overo.^[7]

Interactions

Endothelin receptor type B has been shown to interact with Caveolin 1.^[8]

Ligands

Agonists

• IRL-1620^[9]

Antagonists

• A-192,621
• BQ-788
• Bosentan (unselective ET_A / ET_B antagonist)

See also

• Endothelin receptor

Further reading

• Hofstra RM, Osinga J, Buys CH . Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype . European Journal of Human Genetics . 5 . 4 . 180–5 . 1998 . 9359036 . 10.1159/000484760.
• Haendler B, Hechler U, Schleuning WD . Molecular cloning of human endothelin (ET) receptors ETA and ETB . Journal of Cardiovascular Pharmacology . 20 . S1–4 . 1993 . Suppl 12 . 1282938 . 10.1097/00005344-199204002-00002 . 37973815 . free .
• Arai H, Nakao K, Hosoda K, Ogawa Y, Nakagawa O, Komatsu Y, Imura H . [Molecular cloning of human endothelin receptors and their expression in vascular endothelial cells and smooth muscle cells] . Japanese Circulation Journal . 56 . 1303–7 . 1993 . Suppl 5 . 1291713 . 10.1253/jcj.56.supplementv_1303 . free .
• Ogawa Y, Nakao K, Arai H, Nakagawa O, Hosoda K, Suga S, Nakanishi S, Imura H . Molecular cloning of a non-isopeptide-selective human endothelin receptor . Biochemical and Biophysical Research Communications . 178 . 1 . 248–55 . Jul 1991 . 1648908 . 10.1016/0006-291X(91)91806-N .
• Cyr C, Huebner K, Druck T, Kris R . Cloning and chromosomal localization of a human endothelin ETA receptor . Biochemical and Biophysical Research Communications . 181 . 1 . 184–90 . Nov 1991 . 1659806 . 10.1016/S0006-291X(05)81399-3 . free .
• Nakamuta M, Takayanagi R, Sakai Y, Sakamoto S, Hagiwara H, Mizuno T, Saito Y, Hirose S, Yamamoto M, Nawata H . Cloning and sequence analysis of a cDNA encoding human non-selective type of endothelin receptor . Biochemical and Biophysical Research Communications . 177 . 1 . 34–9 . May 1991 . 1710450 . 10.1016/0006-291X(91)91944-8 .
• Sakamoto A, Yanagisawa M, Sakurai T, Takuwa Y, Yanagisawa H, Masaki T . Cloning and functional expression of human cDNA for the ETB endothelin receptor . Biochemical and Biophysical Research Communications . 178 . 2 . 656–63 . Jul 1991 . 1713452 . 10.1016/0006-291X(91)90158-4 .
• Vane J . Endothelins come home to roost . Nature . 348 . 6303 . 673 . 1991 . 2175394 . 10.1038/348673a0 . 4351182 . free .
• Puffenberger EG, Kauffman ER, Bolk S, Matise TC, Washington SS, Angrist M, Weissenbach J, Garver KL, Mascari M, Ladda R . Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22 . Human Molecular Genetics . 3 . 8 . 1217–25 . Aug 1994 . 7987295 . 10.1093/hmg/3.8.1217 .
• Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravart A . A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease . Cell . 79 . 7 . 1257–66 . Dec 1994 . 8001158 . 10.1016/0092-8674(94)90016-7 . 24894649 .
• Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M . Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons . Cell . 79 . 7 . 1277–85 . Dec 1994 . 8001160 . 10.1016/0092-8674(94)90018-3 . 32577813 .
• Arai H, Nakao K, Takaya K, Hosoda K, Ogawa Y, Nakanishi S, Imura H . The human endothelin-B receptor gene. Structural organization and chromosomal assignment . The Journal of Biological Chemistry . 268 . 5 . 3463–70 . Feb 1993 . 10.1016/S0021-9258(18)53717-0 . 8429023 . free .
• Elshourbagy NA, Korman DR, Wu HL, Sylvester DR, Lee JA, Nuthalaganti P, Bergsma DJ, Kumar CS, Nambi P . Molecular characterization and regulation of the human endothelin receptors . The Journal of Biological Chemistry . 268 . 6 . 3873–9 . Feb 1993 . 10.1016/S0021-9258(18)53554-7 . 8440682 . free .
• Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH . A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome) . Nature Genetics . 12 . 4 . 445–7 . Apr 1996 . 8630503 . 10.1038/ng0496-445 . 1765/54507 . 935271 . free .
• Attié T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, Munnich A, Lyonnet S . Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease . Human Molecular Genetics . 4 . 12 . 2407–9 . Dec 1995 . 8634719 . 10.1093/hmg/4.12.2407 .
• Elshourbagy NA, Adamou JE, Gagnon AW, Wu HL, Pullen M, Nambi P . Molecular characterization of a novel human endothelin receptor splice variant . The Journal of Biological Chemistry . 271 . 41 . 25300–7 . Oct 1996 . 8810293 . 10.1074/jbc.271.41.25300 . free .
• Kusafuka T, Wang Y, Puri P . Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung's disease . Human Molecular Genetics . 5 . 3 . 347–9 . Mar 1996 . 8852658 . 10.1093/hmg/5.3.347 .
• Auricchio A, Casari G, Staiano A, Ballabio A . Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population . Human Molecular Genetics . 5 . 3 . 351–4 . Mar 1996 . 8852659 . 10.1093/hmg/5.3.351 . free .
• Amiel J, Attié T, Jan D, Pelet A, Edery P, Bidaud C, Lacombe D, Tam P, Simeoni J, Flori E, Nihoul-Fékété C, Munnich A, Lyonnet S . Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease . Human Molecular Genetics . 5 . 3 . 355–7 . Mar 1996 . 8852660 . 10.1093/hmg/5.3.355 . free .
• Freedman NJ, Ament AS, Oppermann M, Stoffel RH, Exum ST, Lefkowitz RJ . Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity . The Journal of Biological Chemistry . 272 . 28 . 17734–43 . Jul 1997 . 9211925 . 10.1074/jbc.272.28.17734 . free .
• Mazzuca MQ, Khalil RA . Vascular endothelin receptor type B: structure, function and dysregulation in vascular disease . Biochemical Pharmacology . 84 . 2 . 147–62 . Jul 2012 . 22484314 . 10.1016/j.bcp.2012.03.020 . 3358417 .
• Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ . Endothelin . Pharmacological Reviews . 68 . 2 . 357–418 . April 2016 . 26956245 . 10.1124/pr.115.011833 . 4815360.

External links

• Web site: Endothelin Receptors: ET_B . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Cyr C, Huebner K, Druck T, Kris R . Cloning and chromosomal localization of a human endothelin ETA receptor . Biochemical and Biophysical Research Communications . 181 . 1 . 184–90 . Nov 1991 . 1659806 . 10.1016/S0006-291X(05)81399-3 . free .
2. Web site: Entrez Gene: EDNRB endothelin receptor type B.
3. Sato-Jin K, Nishimura EK, Akasaka E, Huber W, Nakano H, Miller A, Du J, Wu M, Hanada K, Sawamura D, Fisher DE, Imokawa G . Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders . FASEB Journal . 22 . 4 . 1155–68 . Apr 2008 . 18039926 . 10.1096/fj.07-9080com . free . 14304386 .
4. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–76 . Dec 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . free .
5. Tanaka H, Moroi K, Iwai J, Takahashi H, Ohnuma N, Hori S, Takimoto M, Nishiyama M, Masaki T, Yanagisawa M, Sekiya S, Kimura S . Novel mutations of the endothelin B receptor gene in patients with Hirschsprung's disease and their characterization . The Journal of Biological Chemistry . 273 . 18 . 11378–83 . May 1998 . 9556633 . 10.1074/jbc.273.18.11378 . free .
6. Yang GC, Croaker D, Zhang AL, Manglick P, Cartmill T, Cass D . A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease . Human Molecular Genetics . 7 . 6 . 1047–52 . Jun 1998 . 9580670 . 10.1093/hmg/7.6.1047 . AG mutation, which changed isoleucine to lysine in the predicted first transmembrane domain of the EDNRB protein. This was associated with LWFS when homozygous and with the overo phenotype when heterozygous. --> . free .
7. Metallinos DL, Bowling AT, Rine J . A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease . Mamm. Genome . 9 . 6 . 426–31 . 1998 . 9585428 . 10.1007/s003359900790. 19536624 . .
8. Yamaguchi T, Murata Y, Fujiyoshi Y, Doi T . Regulated interaction of endothelin B receptor with caveolin-1 . European Journal of Biochemistry . 270 . 8 . 1816–27 . Apr 2003 . 12694195 . 10.1046/j.1432-1033.2003.03544.x . free .
9. Maguire JJ, Davenport AP . Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12 . British Journal of Pharmacology . 171 . 24 . 5555–72 . Dec 2014 . 25131455 . 10.1111/bph.12874 . 4290702.