Endothelin 2

Last updated
EDN2
Identifiers
Aliases EDN2 , ET2, PPET2, ET-2, endothelin 2
External IDs OMIM: 131241 MGI: 95284 HomoloGene: 1477 GeneCards: EDN2
Orthologs
SpeciesHumanMouse
Entrez

1907

13615

Ensembl

ENSG00000127129

ENSMUSG00000028635

UniProt

P20800

P22389

RefSeq (mRNA)

NM_001956
NM_001302269

NM_007902

RefSeq (protein)

NP_001289198
NP_001947

NP_031928

Location (UCSC) Chr 1: 41.48 – 41.48 Mb Chr 4: 120.02 – 120.02 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Endothelin 2 (ET-2) is a protein encoded by the EDN2 gene in humans. It was first discovered in 1988 by Yanagisawa and team [5] and belongs to a family of three endothelin peptide isoforms (ET-1, ET-2, ET-3), which constrict blood vessels. ET-2 is encoded by genes on separate chromosomes to its isoforms and is mainly produced in vascular endothelial cells of the kidney, placenta, uterus, heart, central nervous system and intestine. [6] It becomes present in the blood of animals and humans at levels ranging from 0.3pg/ml to 3pg/ml. [7] ET-2 acts by binding to two different G-protein coupled receptors (GPCRs), the endothelin A receptor (EDNRA) and the endothelin B receptor (EDNRB). [8]

Contents

Function

As ET-2 has a very similar homology to ET-1, differing only in two amino acids (with Trp6 and Leu7 instead of Leu6 and Met7 [7] ) it was often assumed that the two endothelins were similar in synthetic pathway and mechanism of action. [9] As ET-1 is abundant in the body while ET-2 is almost undetectable, ET-1 was more convenient to research, this assumption has meant ET-2 is relatively under-researched. Equally, limited studies have been conducted using VIC, a vasoactive intestinal peptide and the peptide equivalent to ET-2 in mice. [7]

However, further research evidence suggested distinct roles and features of ET-2. Unlike the other endothelins, ET-2 knockout mice (with the EDN2 gene globally removed from their genetic code) are retarded in growth, hypoglycemic, hypothermic and have ketonemia, resulting in early mortality. These differences between ET-1 and ET-2 may be attributed to differing gene expression and the synthesis of different peptides by endothelin converting enzymes (ECEs). [7]

ET-2 is a potent vasoconstrictor and has been implicated in ovarian physiology, as well as diseases relating to the heart, immunology, and cancers. [7]

Clinical significance

Ovarian follicle rupture

Ovulation occurs at around day 14 of the human menstrual cycle and refers to the release of an egg, characterised by the rupture of a preovulatory ovarian follicle. This process is driven changes in oestrogen-regulated feedback on the hypothalamic-pituitary-gonadal axis, leading to a surge of Luteinising Hormone which drives follicular rupture. [10] There is a complex molecular dialogue for ovulation which involves the coordinated expression of many key proteins, including ET-2. [11]

Within the follicle, ET-2 expression is confined to a group of steroid-producing stromal cells called granulosa cells, where its production peaks transiently at the final stages before ovulation (periovulatory stage). In the mouse, there is a surge of ET-2 around two hours prior to ovulation, this is thought to act as one of the driving forces for follicular rupture. Much of our current understanding of ET-2 and its role during ovulation comes from rodent model experiments. However, there are some interspecies discrepancies, with stark differences identified between the mouse and bovine ovary. [7]

The mechanisms underlying ET-2-induced follicle rupture are debated, with most theories suggesting a mechanical contraction pathway. ET-2 is believed to act on the follicle by binding to and stimulating EDNRA, which is expressed constitutively on the external layer of theca cells (another type of steroid-producing stromal cell). This causes smooth muscle cells surrounding the ovary to contract. [11] This smooth muscle layer encapsulates the ovary but is absent at the site where the oocyte is expelled, creating a region of low surface tension which weakens the follicle wall and promotes the release of an egg. [7]

ET-2 also binds to and activates EDNRB, which is constitutively expressed by granulosa cells and theca interna. There is controversy surrounding the role of ET-2 signalling at this receptor. Some studies suggest that EDNRB activation by ET-2 regulates follicular rupture by antagonising effects of EDNRA stimulation. Alternatively, EDNRB may propel follicular rupture by inducing nitric oxide signalling. This results in local vasodilation, contributing to the rise in follicular fluid pressure seen in the periovulatory phase. [11]

Cardiovascular system

ET-2, like ET-1, has a role in modulating vascular tone. [7] This can have implications for blood pressure control. A specific EDN2 gene polymorphism has been correlated with essential hypertension and alternative studies have shown associations between certain rare ET-2 polymorphisms and lower diastolic blood pressures. [7] The ET-2 gene has been shown to co-segregate with blood pressure in rodent studies; a potential reason for the link. [12]

However, transgenic rats expressing the human ET-2 gene under the control of the human endothelin promotor are normotensive (blood pressure in normal range), despite these studies suggesting that overexpression of ET-2 results in glomerulosclerosis. [7] [12] This suggests that further investigation into the role of ET-2 in blood pressure is warranted.

As a strong positive inotrope, endothelin-2 has an impact on the human myocardium and for this reason, endothelin-2 antagonists have been shown to improve exercise tolerance and inhibit clinical deterioration in pulmonary hypertension. [7] ET-2 demonstrates a positive chronotropic and proarrhythmic effects. A study showed a significant association of a specific polymorphism of the EDN2 gene with increased incidence of atrial fibrillation in patients with hypertrophic cardiomyopathy. [12] Overall, the evidence suggests that ET-2 could modulate vascular tone, tissue morphology and remodelling. [12]

Breast tumour cell invasion

Since reports of increased ET-2 expression in human breast cancer (2002), there has been growing interest in ET-2 within cancer pathogenesis. [7] There is increased expression of the ‘endothelin axis’ consisting of 21 amino acid peptides (ET-1, ET-2 and ET-3), two GPCRs and two activating peptidases in invasive breast cancer. [13] This increased expression is not seen in non-invasive tissue. [13] This is further supported by observations from patient biopsies, endothelin expression is associated specifically with regions of the tumour that are invasive and is more common in whole tumours with lymphovascular invasion (i.e. the invasion of cancer cells into the lymphatic system). [13]

In vitro, when breast tumour cell lines with endothelins are stimulated, the phenotype becomes invasive. [13] Invasion through an artificial membrane can be stimulated, particularly when co-cultured in the presence of macrophages. [13] The association between endothelins, poor prognosis and invasion suggests the endothelin axis is an interesting therapeutic target for the treatment of invasive breast cancer. [13]

The breast tumour microenvironment is particularly hypoxic which allows it to modulate the expression of numerous ‘pro-tumour’ genes including endothelins. This hypoxic environment can be replicated in vitro, resulting in increased expression of ET-2 by breast tumour cells. [13] This increased ET-2 expression provides the tumour with autocrine protection from hypoxia-associated apoptosis allowing growth of the tumour. [13] Further research using mice with breast tumours in hypoxic conditions showed that the addition of ET-2 increased the survival of tumour cells suggesting the upregulation of ET-2 in hypoxic tumours may explain the increased invasive potential and worse prognosis than their well oxygenated counterparts. [7]

Related Research Articles

<span class="mw-page-title-main">Ovarian follicle</span> Structure containing a single egg cell

An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with the potential to release an egg cell (ovum) at ovulation for fertilization. These eggs are developed once every menstrual cycle with around 450–500 being ovulated during a woman's reproductive lifetime.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<span class="mw-page-title-main">Endothelin</span>

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

<span class="mw-page-title-main">Growth differentiation factor-9</span> Protein-coding gene in the species Homo sapiens

Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.

<span class="mw-page-title-main">Follicular atresia</span>

Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.

<span class="mw-page-title-main">Follicle-stimulating hormone receptor</span> Protein-coding gene in the species Homo sapiens

The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.

<span class="mw-page-title-main">CCL8</span> Mammalian protein found in Homo sapiens

Chemokine ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.

<span class="mw-page-title-main">CXCR5</span> Mammalian protein found in Homo sapiens

C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 and belongs to the CXC chemokine receptor family. It enables T cells to migrate to lymph node and the B cell zones. In humans, the CXC-R5 protein is encoded by the CXCR5 gene.

<span class="mw-page-title-main">Epiregulin</span> Protein found in humans

Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.

<span class="mw-page-title-main">Gastrin-releasing peptide receptor</span> Protein-coding gene in the species Homo sapiens

The gastrin-releasing peptide receptor (GRPR), now properly known as BB2 is a G protein-coupled receptor whose endogenous ligand is gastrin releasing peptide. In humans it is highly expressed in the pancreas and is also expressed in the stomach, adrenal cortex and brain.

<span class="mw-page-title-main">RAC3</span> Mammalian protein found in Homo sapiens

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

<span class="mw-page-title-main">GPR183</span>

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

<span class="mw-page-title-main">Endothelin B receptor</span> Protein-coding gene in the species Homo sapiens

Endothelin receptor type B, also known as ETB is a protein that in humans is encoded by the EDNRB gene.

<span class="mw-page-title-main">LGR5</span>

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.

<span class="mw-page-title-main">HLA-F</span>

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include INF-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.

<span class="mw-page-title-main">Endothelin 3</span> Protein-coding gene in the species Homo sapiens

Endothelin-3 is a protein that in humans is encoded by the EDN3 gene.

<span class="mw-page-title-main">Tumor necrosis factor receptor 2</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα). Like its counterpart, tumor necrosis factor receptor 1 (TNFR1), the extracellular region of TNFR2 consists of four cysteine-rich domains which allow for binding to TNFα. TNFR1 and TNFR2 possess different functions when bound to TNFα due to differences in their intracellular structures, such as TNFR2 lacking a death domain (DD).

TOX high mobility group box family member 3, also known as TOX3, is a human gene.

FDC-SP or follicular dendritic cell-secreted protein, is a small, secreted protein, located on chromosome 4 in humans. It is thought to play an immune role in the junctional epithelium at the gingival crevice in the human mouth. It is very similar in structure to statherin, a protein contained in saliva.

<span class="mw-page-title-main">FOXA1</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000127129 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028635 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. (March 1988). "A novel potent vasoconstrictor peptide produced by vascular endothelial cells". Nature. 332 (6163): 411–5. Bibcode:1988Natur.332..411Y. doi:10.1038/332411a0. hdl: 2241/1639 . PMID   2451132. S2CID   4308549.
  6. ↑ Vatta MS, Bianciotti LG, Guil MJ, Hope SI (2015). "Regulation of the norepinephrine transporter by endothelins: a potential therapeutic target". Vitamins and Hormones. 98: 371–405. doi:10.1016/bs.vh.2014.12.013. ISBN   978-0-12-803008-0. PMID   25817875.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 Ling L, Maguire JJ, Davenport AP (January 2013). "Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer". British Journal of Pharmacology. 168 (2): 283–95. doi:10.1111/j.1476-5381.2011.01786.x. PMC   3572556 . PMID   22118774.
  8. ↑ Nakas-Ićindić E, Zaciragić A, Hadzović A, Avdagić N (July 2004). "Endothelin in health and disease". Bosnian Journal of Basic Medical Sciences. 4 (3): 31–4. doi:10.17305/bjbms.2004.3381. PMC   7245481 . PMID   15629009.
  9. ↑ Binz N, Rakoczy EP, Ali Rahman IS, Vagaja NN, Lai CM (2016-08-02). Knut S (ed.). "Biomarkers for Diabetic Retinopathy - Could Endothelin 2 Be Part of the Answer?". PLOS ONE. 11 (8): e0160442. Bibcode:2016PLoSO..1160442B. doi: 10.1371/journal.pone.0160442 . PMC   4970817 . PMID   27482904.
  10. ↑ Robker RL, Hennebold JD, Russell DL (September 2018). "Coordination of Ovulation and Oocyte Maturation: A Good Egg at the Right Time". Endocrinology. 159 (9): 3209–3218. doi:10.1210/en.2018-00485. PMC   6456964 . PMID   30010832.
  11. 1 2 3 Ko C, Meidan R, Bridges PJ (October 2012). "Why two endothelins and two receptors for ovulation and luteal regulation?". Life Sciences. 91 (13–14): 501–6. doi: 10.1016/j.lfs.2012.05.010 . PMID   22677434.
  12. 1 2 3 4 Krämer BK, Ittner KP, Beyer ME, Hoffmeister HM, Riegger GA (1997-11-01). "Circulatory and myocardial effects of endothelin". Journal of Molecular Medicine. 75 (11–12): 886–90. doi:10.1007/s001090050180. PMID   9428621. S2CID   8300313.
  13. 1 2 3 4 5 6 7 8 Grimshaw MJ (May 2005). "Endothelins in breast tumour cell invasion". Cancer Letters. 222 (2): 129–38. doi:10.1016/j.canlet.2004.08.029. PMID   15863261.

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