Endothelin

Overview: Endothelin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Endothelin Receptors, Davenport, 2002) are activated by the endogenous 21 amino-acid peptides endothelin-1 (ET-1, ENSG00000078401), ET-2 (ENSG00000127129) and ET-3 (ENSG00000124205). Non-selective peptide (e.g. TAK044, pA₂ 8.4) and non-peptide (e.g. bosentan, pA₂ 6.0–7.2; SB209670, pA₂ 9.4) antagonists can block both ET_A and ET_B receptors. Splice variants of the ET_A receptor have been identified in rat pituitary cells; one of these, ET_AR-C13, appeared to show loss of function with comparable plasma membrane expression (Hatae et al., 2007).

Nomenclature	ETA	ETB
Ensembl ID	ENSG00000151617	ENSG00000136160
Principal transduction	Gq/11, Gs	Gq/11, Gi/o
Potency order	ET-1, ET-2 > ET-3 (Maguire and Davenport, 1995)	ET-1, ET-2, ET-3
Selective agonists	–	[Ala1,3,11,15]ET-1 (Molenaar et al., 1992), sarafotoxin S6c (Russell and Davenport, 1996), IRL1620 (Watakabe et al., 1992), BQ3020 (Russell and Davenport, 1996)
Selective antagonists	A127722 (9.2–10.5, Opgenorth et al., 1996), LU135252 (8.9, Riechers et al., 1996), SB234551 (8.7–9.0, Ohlstein et al., 1998), PD156707 (8.2–8.5, Maguire et al., 1997), FR139317 (7.3–7.9, Maguire and Davenport, 1995), BQ123 (6.9–7.4, Maguire and Davenport, 1995), ZD4054 (pIC50 8.3, Morris et al., 2005)	BQ788 (8.4, Russell and Davenport, 1996), A192621 (8.1, von Geldern et al., 1999), IRL2500 (7.2, Russell and Davenport, 1996), Ro468443 (7.1, Breu et al., 1996)
Probes	[3H]-S0139 (0.6 nM), [3H]-BQ123 (3.2 nM, Ihara et al., 1995), [125I]-PD164333 (0.2 nM, Davenport et al., 1998), [125I]-PD151242 (0.5 nM, Davenport et al., 1994)	[125I]-IRL1620 (20 pM, Watakabe et al., 1992), [125I]-BQ3020 (0.1 nM, Molenaar et al., 1992), [125I]-[Ala1,3,11,15]ET-1 (0.2 nM, Molenaar et al., 1992)

Subtypes of the ET_B receptor have been proposed, although gene disruption studies in mice suggest that the heterogeneity results from a single gene product (Mizuguchi et al., 1997).

Glossary

Abbreviations:

A127722

trans-trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-([N,N-dibutylamino]carbonylmethyl)pyrrolidine-3-carboxylate

A192621

(2R,3R,4S)-2-(4-propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-[2,6-diethylphenyl]acetamido)pyrrolidine-3-carboxylic acid

BQ123

cyc(DTrp-DAsp-Pro-D-Val-Leu)

BQ3020

N-acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp

BQ788

N-cis-2,6-dimethylpiperidinocarbonyl-L-γ-methylleucyl-D-1-methoxycarboyl-D-norleucine

FR139317

(R)2-([R-2-{(S)-2-([1-{hexahydro-1H-azepinyl}carbonyl]amino)methyl}pentanoyl]amino-3-(3-[methyl-1H-indodyl])propionylamino-3-(2-pyridyl))propionate

IRL1620

Suc[Glu⁹,Ala^11,15]ET-1_10–21

IRL2500

N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-Ala-Trp

LU135252

(+)-(S)-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-propionic acid

PD151242

(N-[{hexahydro-1-azepinyl}carbonyl])Leu(1-Me)-DTrp-DTyr

PD156707

2-benzo[1,3]dioxol-5-yl-4-(4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-but-2-enoate

PD164333

2-benzo[1,3]dioxol-5-yl-4-(3-[2-(4-hydroxy-phenyl)-ethylcarbamoyl]-propoxy)-4,5-dimethoxy-phenyl-3-(4-methoxy-benzoyl)-but-2-enoate

RES7011

cyc(Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp)-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp

Ro468443

(R)-4-tert-butyl-N-(6-[2,3-dihydroxypropoxy]-5-[2-methoxyphenoxy]-2-[4-methoxyphenyl]-pyrimidin-4-yl)-benzenesulfonamide

S0139

27-O-3-(2-[3-carboxyacryloylamino]-5-hydroxyphenyl)-acryloyloxymyricone, sodium salt

SB209670

(+)-1S,2R,S-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxyindane-2-carboxylate

SB234551

(E)-α-([1-butyl-5-{2-([2-carboxyphenyl]methoxy)-4-methoxyphenyl}-1H-pyrazol-4-yl]methylene)-6-methoxy-1,3-benzodioxole-5-propanoic acid

TAK044

cyc(D-Asp-Asp(Php)-Asp-D-Thg-Leu-D-Trp)-4-oxobut-2-enoate

ZD4054

N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide

Further Reading

Bagnato A, Rosano L (2008). The endothelin axis in cancer. Int J Biochem Cell Biol40: 1443–1451.

Davenport AP (2002). International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev54: 219–226.

Davenport AP, Maguire JJ (2006). Endothelin. Handb Exp Pharmacol176: 295–329.

Dhaun N, Pollock DM, Goddard J, Webb DJ (2007). Selective and mixed endothelin receptor antagonism in cardiovascular disease. Trends Pharmacol Sci28: 573–579.

Dhaun N, Goddard J, Kohan DE, Pollock DM, Schiffrin EL, Webb DJ (2008). Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension52: 452–459.

Dupuis J, Hoeper MM (2008). Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J31: 407–415.

Khodorova A, Montmayeur JP, Strichartz G (2009). Endothelin receptors and pain. J Pain10: 4–28.

Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ (2008). The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol153: 1105–1119.

Motte S, McEntee K, Naeije R (2006). Endothelin receptor antagonists. Pharmacol Ther110: 386–414.

Schinelli S (2006). Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem13: 627–638.

Schneider MP, Boesen EI, Pollock DM. (2007). Contrasting actions of endothelin ET_A and ET_B receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol47: 731–759.

Schorlemmer A, Matter ML, Shohet RV (2008). Cardioprotective signaling by endothelin. Trends Cardiovasc Med18: 233–239.