Endothelin receptors: Introduction


In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2 and ET-3 [20,43], and the receptors that mediate their effects have been classified as the endothelin ETA and ETB receptors.

Receptor structure

The two endothelin receptors have been isolated and cloned from mammalian tissues [1-2,6,20,24,28,32-33,43]. The structures of the mature receptors have been deduced from the nucleotide sequences of the cDNAs. The encoded proteins contain seven stretches of 20-27 hydrophobic amino acid (aa) residues in both receptors. This structure is consistent with a seven-transmembrane domain (7TM), G protein-coupled receptor belonging to the rhodopsin-type receptor superfamily. Both receptors have an N-terminal signal sequence, which is rare among heptahelical receptors, with a relatively long extracellular N-terminal portion preceding the first transmembrane domain. There are two separate ligand-interaction sub-domains on each endothelin receptor. The extracellular loops, particularly between TM4-TM6, determine selectivity.

Receptor signalling

Endothelin is able to activate a number of signal transduction processes including phospholipase (PL) A2, PLC and PLD, as well as cytosolic protein kinase activation. The receptors are able to couple to various types of G protein. Both ETA and ETB receptors expressed in COS7 cells were shown to couple to Gq, G11, Gs and Gi2, suggesting that endothelin receptors may simultaneously stimulate multiple effectors via several types of G protein [37]. ETA receptors expressed in CHO cells couple to Gq and Gs but not Gi. ETB receptors couple to Gq and Gi. Coupling to Gs occurs through the second and third intracellular loops of the receptor. In order to couple with Gi through the third intracellular loop, palmitoylation of the C-terminal cysteine residues and C-terminus are necessary, whereas to couple with Gq only palmitoylation of the C-terminal domain is important [3,16].


Endothelin receptors are widely expressed in all tissues, consistent with the physiological role of endothelins as ubiquitous endothelium-derived vasoactive peptides, contributing to the maintenance of vascular tone. Receptors are also localised to non-vascular structures such as epithelial cells as well as occurring in the central nervous system (CNS) on glia and neurones. Both ETA and ETB receptors are widely distributed, particularly in blood vessels. In human vessels, ETA receptors are mainly located on vascular smooth muscle cells, with ETB receptors being present on endothelial cells lining the vessel wall. ETB receptors may play a role in the release of endothelium-derived relaxing factors such as nitric oxide (NO) and prostanoids from endothelial cells [40] where all three isoforms have a similar potency [11]. ETA receptors present on smooth muscle cells are mainly responsible for contraction, but in animals this can vary depending on the species and vascular bed. In some blood vessels such as the rabbit saphenous vein, the rabbit jugular vein, rat renal vascular bed and porcine pulmonary vein, ETB receptors mediate vasoconstriction. In other vessels, ET-1 is thought to mediate vasoconstriction by activating both receptors. Endothelin stimulates proliferation in a number of different cell types including smooth muscle cells (mainly via the ETA receptor) or astrocytes (ETB receptor). In most of these cells, endothelin is thought to be co-mitogenic, potentiating the actions of other growth factors such as PDGF.


A selective ETA receptor agonist has not been discovered to date. Sarafotoxin S6c [41] is a selective ETB receptor agonist, as is [Ala1,3,11,15]ET-1 [31], a linear analogue of ET-1 in which the disulphide bridges have been removed by substitution of Ala for Cys residues. ETB receptors also bind the truncated alanine analogues BQ3020 ([Ala11,15]Ac-ET-1(6-21)) [18] and IRL1620 (Suc-(Glu9, Ala11,15)-ET-1(8-21)) [36]. Both compounds have been radiolabelled to give ligands that are highly selective and bind with sub-nanomolar affinity [27]. These peptides have the same or similar amino acid sequences in the C-terminus compared with ET-1. The compounds cause endothelium-dependent vasodilatation, in preparations such as porcine pulmonary artery, consistent with ETB receptor-mediated release of relaxing factors from the endothelium.

The cyclic pentapeptide, BQ123 (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp-]) [17] is a highly selective ETA receptor antagonist which has been radiolabelled [19]. This compound, and related cyclic peptides, was originally derived from BE18257 (cyclo-[D-Glu-L-Ala-allo-D-lle-L-Leu-D-Trp-]), a natural product of Streptomyces misakiensis. The modified linear peptide FR139317 (N-[(hexahydro-1-azepinyl)carbonyl]L-Leu(1-Me)D-Trp-3(2-pyridyl)-D-Ala [4] is also a selective ETA receptor antagonist, and a structurally similar selective radioligand, [125l]-PD151242 has been developed [10]. Non-peptide ETA receptor-selective antagonists include PD155080 [25], PD156707 [12], SB234551 [29], L754142 [42], BMS182874 [35] and A127722 [30]. Unlike peptide antagonists, most of these compounds have good oral activity and some may cross the blood brain barrier. IRL2500 [5], RES7011 [38], BQ788 [21] (peptides) and Ro 46-8443 [7] (non-peptide) are selective ETB receptor antagonists. Antagonists that block both ETA and ETB receptors include the peptide TAK044 [23] and the non-peptide compounds bosentan [9] and SB209670 [14].

Other receptors

The existence of alternative splice variants of the ETB receptor has been reported. Cheng et al. [8] identified a novel cDNA from rat brain which produced a receptor protein with four amino acid substitutions. A variant ETB receptor that results in a 10aa increase in the length of the second cytoplasmic domain has been described [34]. However, this did not result in any change in ligand affinities and the physiological importance is unclear. Elshourbagy et al. [15] discovered a splice variant from a human placental library; sequence analysis indicated the deduced polypeptide consisted of 436aa and had 91% sequence similarity to the known human ETB receptor (442aa). However, although the variant displayed the same ligand binding properties of the wild-type, no functional response was detected. The cloning of an ET-3 specific receptor (ET-3 > ET-1) has been described from Xenopus laevis dermal melanophores [22]. The amino acid sequence had 47% sequence homology to the bovine ETA receptor and 52% homology with the rat ETB receptor, but no mammalian homologue has yet been identified.

Functional studies have suggested that PD142893 (AC-(Beta-Phynyl) D-Phe-L-Leu-L-Asp-L-lle-L-lle-L-Trp, a hexapeptide antagonist) can block the vasodilator actions of ET-1 at endothelial ETB receptors but not constrictor responses mediated by ETB smooth muscle receptors [13,39]. However, in the ETB receptor gene knock-out mouse, both the PD142893-sensitive vasodilator response and the PD142893-resistant contractile response to the ETB agonist S6c were completely absent. These results indicate that the pharmacologically heterogeneous responses to S6c are mediated by ETB receptors derived from the same gene [26].


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