Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
10  structures 109  species 1  interaction 317  sequences 4  architectures

Family: Endothelin (PF00322)

Summary: Endothelin family

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Endothelin". More...

Endothelin Edit Wikipedia article

Endothelin family
1EDN human endothelin1 02.png
Symbol Endothelin
Pfam PF00322
InterPro IPR001928
SCOP 1edp
OPM superfamily 156
OPM protein 3cmh
Endothelin 1
Symbol EDN1
Entrez 1906
HUGO 3176
OMIM 131240
RefSeq NM_001955
UniProt P05305
Other data
Locus Chr. 6 p23-p24
Endothelin 2
Symbol EDN2
Entrez 1907
HUGO 3177
OMIM 131241
RefSeq NM_001956
UniProt P20800
Other data
Locus Chr. 1 p34
Endothelin 3
Symbol EDN3
HUGO 3178
OMIM 131242
RefSeq NM_000114
UniProt P14138
Other data
Locus Chr. 20 q13.2-q13.3

Endothelins are peptides with receptors and effects in many body organs.[1][2] 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.[1][3]

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain.[4][5] As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems.[1][6][7][8]


Endothelins derived the name from their isolation in cultured endothelial cells.[1][9]


There are three isoforms of the peptide (identified as ET-1, -2, -3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[1][10]


Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788.[9] An ETA-selective antagonist, ambrisentan was approved for treatment of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver.[1] Bosentan was a precursor to macitentan, which was approved in 2013.[1]

Physiological effects

Endothelins are the most potent vasoconstrictors known.[1][11] Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan.[1]

Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[12] which display increased metabolic activity when exposed to endothelin-1 in the blood or ventricular system.[13]

ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[14] The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.[14]

The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.[15]

Disease involvement

The ubiquitous distribution of endothelin peptides and receptors implicates its involvement in a wide variety of physiological and pathological processes in the body.[1] Among numerous diseases potentially occurring from endothelin dysregulation are

In insulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevates blood pressure.[19]

ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.[20]

In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in specified interconnected circuits of the brain, and to induce convulsions, indicating its potential for diverse neural effects in conditions such as epilepsy.[21]

Gene regulation

The endothelium regulates local vascular tone and integrity through the coordinated release of vasoactive molecules. Secretion of endothelin-1 (ET-1)1 from the endothelium signals vasoconstriction and influences local cellular growth and survival. ET-1 has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension. Endothelial cells upregulate ET-1 in response to hypoxia, oxidized LDL, pro-inflammatory cytokines, and bacterial toxins. Initial studies on the ET-1 promoter provided some of the earliest mechanistic insight into endothelial-specific gene regulation. Numerous studies have since provided valuable insight into ET-1 promoter regulation under basal and activated cellular states.

The ET-1 mRNA is labile with a half-life of less than an hour. Together, the combined actions of ET-1 transcription and rapid mRNA turnover allow for stringent control over its expression. It has previously been shown that ET-1 mRNA is selectively stabilized in response to cellular activation by Escherichia coli O157:H7-derived verotoxins, suggesting ET-1 is regulated by post-transcriptional mechanisms. Regulatory elements modulating mRNA half-life are often found within 3'-untranslated regions (3'-UTR). The 1.1-kb 3'-UTR of human ET-1 accounts for over 50% of the transcript length and features long tracts of highly conserved sequences including an AU-rich region. Some 3'-UTR AU-rich elements (AREs) play important regulatory roles in cytokine and proto-oncogene expression by influencing half-life under basal conditions and in response to cellular activation. Several RNA-binding proteins with affinities for AREs have been characterized including AUF1 (hnRNPD), the ELAV family (HuR, HuB, HuC, HuD), tristetraprolin, TIA/TIAR, HSP70, and others. Although specific mechanisms directing ARE activity have not been fully elucidated, current models suggest ARE-binding proteins target specific mRNAs to cellular pathways that influence 3'-polyadenylate tail and 5'-cap metabolism.

Recent studies have revealed a functional link between AUF1, heat shock proteins and the ubiquitin-proteasome network. Proteasome inhibition by chemical inhibition or heat shock was shown to stabilize a model ARE-containing mRNA whereas promotion of cellular ubiquitination pathways was shown to accelerate ARE mRNA turnover. Studies with in vitro proteasome preparations suggest that the proteasome itself may possess ARE-specific RNA destabilizing activity. The ARE-binding protein AUF1 has been linked to the ubiquitin-proteasome pathway. AUF1 mRNA destabilizing activity has been positively correlated with its level of polyubiquitination and has been shown to interact with a member of the E2 ubiquitin-conjugating protein family. Furthermore, under conditions of cellular heat shock AUF1 associates with heat shock protein 70 (HSP70), which itself possesses ARE binding activity.

The ET-1 transcript is constitutively destabilized by its 3'-UTR through two destabilizing elements, DE1 and DE2. DE1 functions through a conserved ARE by the AUF1-proteasome pathway and is regulated by the heat shock pathway.[22]


  1. ^ a b c d e f g h i j k Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ (April 2016). "Endothelin". Pharmacological Reviews. 68 (2): 357–418. doi:10.1124/pr.115.011833. PMC 4815360Freely accessible. PMID 26956245. 
  2. ^ Kedzierski RM, Yanagisawa M (2001). "Endothelin system: the double-edged sword in health and disease". Annual Review of Pharmacology and Toxicology. 41: 851–76. doi:10.1146/annurev.pharmtox.41.1.851. PMID 11264479. 
  3. ^ Maguire JJ, Davenport AP (December 2014). "Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12". British Journal of Pharmacology. 171 (24): 5555–72. doi:10.1111/bph.12874. PMC 4290702Freely accessible. PMID 25131455. 
  4. ^ Agapitov AV, Haynes WG (March 2002). "Role of endothelin in cardiovascular disease". Journal of the Renin-Angiotensin-Aldosterone System. 3 (1): 1–15. doi:10.3317/jraas.2002.001. PMID 11984741. 
  5. ^ Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Current Medicinal Chemistry. 13 (6): 627–38. doi:10.2174/092986706776055652. PMID 16529555. 
  6. ^ Kuang HY, Wu YH, Yi QJ, Tian J, Wu C, Shou WN, Lu TW (March 2018). "The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis". Medicine. 97 (10): e0075. doi:10.1097/MD.0000000000010075. PMID 29517668. 
  7. ^ Iljazi A, Ayata C, Ashina M, Hougaard A (March 2018). "The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review". Current Pain and Headache Reports. 22 (4): 27. doi:10.1007/s11916-018-0682-8. PMID 29557064. 
  8. ^ Lu YP, Hasan AA, Zeng S, Hocher B (2017). "Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies". Kidney and Blood Pressure Research. 42 (4): 654–663. doi:10.1159/000482004. PMID 29212079. 
  9. ^ a b Tuma RF, Durán WN, Ley K (2008). Microcirculation (2nd ed.). Amsterdam: Elsevier/Academic Press. pp. 305–307. ISBN 978-0-12-374530-9. 
  10. ^ Boron WF, Boulpaep EL (2009). Medical physiology a cellular and molecular approach (2nd International ed.). Philadelphia, PA: Saunders/Elsevier. p. 480. ISBN 978-1-4377-2017-4. 
  11. ^ Craig CR, Stitzel RE (2004). Modern pharmacology with clinical applications (6th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 215. ISBN 978-0-7817-3762-3. 
  12. ^ Lange M, Pagotto U, Renner U, Arzberger T, Oeckler R, Stalla GK (May 2002). "The role of endothelins in the regulation of pituitary function". Experimental and Clinical Endocrinology & Diabetes. 110 (3): 103–12. doi:10.1055/s-2002-29086. PMID 12012269. 
  13. ^ Gross PM, Wainman DS, Espinosa FJ (August 1991). "Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1". Endocrinology. 129 (2): 1110–2. doi:10.1210/endo-129-2-1110. PMID 1855455. 
  14. ^ a b Böhm F, Pernow J (2007). "The importance of endothelin-1 for vascular dysfunction in cardiovascular disease" (PDF). CARDIOVASCULAR RESEARCH. 76 (1): 8–18. doi:10.1016/j.cardiores.2007.06.004. PMID 17617392. 
  15. ^ Kakutani M, Masaki T, Sawamura T (2000). "A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1". Proceedings of the National Academy of Sciences of the United States of America. 97 (1): 360–364. doi:10.1016/j.biochi.2016.10.010. PMC 26668Freely accessible. PMID 10618423. 
  16. ^ Bagnato A, Rosanò L (2008). "The endothelin axis in cancer". The International Journal of Biochemistry & Cell Biology. 40 (8): 1443–51. doi:10.1016/j.biocel.2008.01.022. PMID 18325824. 
  17. ^ Macdonald RL, Pluta RM, Zhang JH (May 2007). "Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution". Nature Clinical Practice Neurology. 3 (5): 256–63. doi:10.1038/ncpneuro0490. PMID 17479073. 
  18. ^ Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M (2005). "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience. 130 (2): 349–58. doi:10.1016/j.neuroscience.2004.09.036. PMID 15664691. 
  19. ^ Potenza MA, Addabbo F, Montagnani M (September 2009). "Vascular actions of insulin with implications for endothelial dysfunction". American Journal of Physiology. Endocrinology and Metabolism. 297 (3): E568–77. doi:10.1152/ajpheart.00297.2016. PMID 19491294. 
  20. ^ Shemyakin A, Salehzadeh F, Böhm F, Al-Khalili L, Gonon A, Wagner H, Efendic S, Krook A, Pernow J (May 2010). "Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro". The Journal of Clinical Endocrinology and Metabolism. 95 (5): 2359–66. doi:10.1210/jc.2009-1506. PMID 20207830. 
  21. ^ Chew BH, Weaver DF, Gross PM (May 1995). "Dose-related potent brain stimulation by the neuropeptide endothelin-1 after intraventricular administration in conscious rats". Pharmacology Biochemistry and Behavior. 51 (1): 37–47. PMID 7617731. 
  22. ^ Mawji IA, Robb GB, Tai SC, Marsden PA (March 2004). "Role of the 3'-untranslated region of human endothelin-1 in vascular endothelial cells. Contribution to transcript lability and the cellular heat shock response". The Journal of Biological Chemistry. 279 (10): 8655–67. doi:10.1074/jbc.M312190200. PMID 14660616. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Endothelin family Provide feedback

No Pfam abstract.

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001928

Endothelins (ET's) are the most potent vasoconstrictors known [PUBMED:2690429, PUBMED:2168326, PUBMED:1916094]. They stimulate cardiac contraction, regulate release of vasoactive substances, and stimulate mitogenesis in blood vessels in primary culture. They also stimulate contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferensa and stomach) and stimulate secretion in several tissues (e.g., kidney, liver and adrenals). Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells. Endothelins have been implicated in a variety of pathophysiological conditions associated with stress, including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure.

Endothelins are synthesised by proteolysis of large preproendothelins, which are cleaved to 'big endothelins' before being processed to the mature peptide.

Sarafotoxins (SRTX) and bibrotoxin (BTX) are cardiotoxins from the venom of snakes of the Atractaspis family, structurally and functionally [PUBMED:2549664, PUBMED:1656557] similar to endothelin.

As shown in the following schematic representation, these peptides which are 21 residues long contain two intramolecular disulphide bonds.

                        |             |
                          |       |
'C': conserved cysteine involved in a disulphide bond.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View  View   
HTML View  View               
PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: endothelin;
Type: Repeat
Sequence Ontology: SO:0001068
Author: Finn RD
Number in seed: 6
Number in full: 317
Average length of the domain: 28.60 aa
Average identity of full alignment: 78 %
Average coverage of the sequence by the domain: 15.69 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.8 36.3
Noise cut-off 20.4 20.3
Model length: 29
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Endothelin domain has been found. There are 10 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

Loading structure mapping...