The current endothelin receptor classification: time for reconsideration?

doi:10.1016/0165-6147(94)90159-7

Trends in Pharmacological Sciences

Volume 15, Issue 10, October 1994, Pages 379-386

https://doi.org/10.1016/0165-6147(94)90159-7 Get rights and content

Abstract

The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of endothelin research has resulted in the molecular characterization and pharmacological recognition of ET_A and ET_B receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ET_A or ET_B receptors. In this article. Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular.

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Differences in endothelin receptor types in the vasculature of Bothrops jararaca (Viperidae) and Oxyrhopus guibei (Colubridae) snakes
2008, Comparative Biochemistry and Physiology - C Toxicology and Pharmacology
Endothelins (ETs) are vasoactive peptides evolutionary well conserved that exert their effects through two specific receptors (ET_A and ET_B) widely distributed in all vertebrates. In snakes, the presence and function of endothelins and their receptors are still scarcely described. We have recently demonstrated the presence of ET_A and ET_B2 receptors in the snake Bothrops jararaca (Bj). In the present work we showed that distinctively from Bj, the vascular contraction induced by endothelin in Oxyrhopus guibei (Og) snake is mediated only by ET_A receptors. Selective ET_B agonists (SRTX-c and IRL₁₆₂₀) and antagonists (IRL₁₀₃₈ and BQ₇₈₈) were ineffective in Og preparations of isolated aorta. We also showed that ET-1 response on Og arterial blood pressure was monophasic hypertensive as opposed to biphasic (hypotension followed by hypertension) in Bj. Furthermore, we characterized the relaxing properties of endothelin receptor ET_B1 in pre-contracted aorta preparations. We showed that IRL₁₆₂₀ induced relaxation of pre-contracted Bj aorta but was ineffective in relaxing Og preparations. IRL₁₆₂₀ relaxing effect on Bj aorta was abolished by l-NAME, indicating involvement of NO release, and was reduced by selective ET_B antagonists. Our findings suggest that Og snake has a more primitive spectrum of ET receptors (only ET_A receptor) than Bj (presence of ET_A, ET_B1 and ET_B2 receptors).
Correlation between vascular responsivensss and expression of novel transcripts of the ET<inf>A</inf>-receptor in human vascular tissue
2007, Vascular Pharmacology
Citation Excerpt :
Specific receptor subtypes for ET-1 encoded by separate genes are responsible for vasoconstriction (ETA and ETB receptors), vasodilatation via the release of vasoactive agents from the endothelium (ETB receptors) and mitogenesis (ETA receptors) (Galie et al., 2004). However, a number of observations relating to the effect of ETA receptor antagonists that do not fit with the current receptor classification remain unresolved (Bax and Saxena, 1994). These discrepancies are especially evident in studies with human blood vessels.
Alternatively spliced endothelin (ET-1) receptor transcripts have been identified, but their significance to the functional effects of ET-1 has not been established. We have investigated the presence and influence of alternatively spliced ET_A receptor transcripts on ET-1 mediated contraction of segments of human saphenous vein. The expression of ET_A receptor transcripts was examined with quantitative reverse transcription-polymerase chain reaction (qPCR) studies, while the response of veins to ET-1 was tested with in vitro organ bath techniques. The expression of four different transcripts for the ET_A receptor, in which either exon 3 is spliced out (Δ3), exon 4 is spliced out (Δ4), both 3 and 4 spliced out (Δ3,4) and when both exons 2 and 4 (Δ2,4) are spliced out were identified. Functional studies showed that a lack of efficacy and potency of ET-1 is associated with a significantly lower expression of the Δ3,4 transcript. ET_A receptor antagonism was insurmountable in samples that had lower levels of the Δ3,4 transcript, while samples from patients with higher expression of the Δ3,4 showed surmountable antagonism with BQ123. These results suggest that there is a genetic basis for the variability between individuals for the contractile effect of ET-1 at ET_A receptors.
Solution Structures of the SURP Domains and the Subunit-Assembly Mechanism within the Splicing Factor SF3a Complex in 17S U2 snRNP
2006, Structure
Citation Excerpt :
1H, 15N, and 13C chemical shifts were referenced relative to the frequency of the 2H lock resonance of water. Main-chain and side-chain assignments were obtained from a combination of standard triple resonance experiments (Bax and Saxena, 1994; Kay, 1997). 2D [1H, 15N]-HSQC and 3D [1H, 15N, 13C]-HNCO, HN(CA)CO, HNCA, HN(CO)CA, HNCACB, and CBCA(CO)NH spectra were used for the 1H, 15N, and 13C assignments of the main chain.
The SF3a complex, consisting of SF3a60, SF3a66, and SF3a120, in 17S U2 snRNP is crucial to spliceosomal assembly. SF3a120 contains two tandem SURP domains (SURP1 and SURP2), and SURP2 is responsible for binding to SF3a60. We found that the SURP2 fragment forms a stable complex with an SF3a60 fragment (residues 71–107) and solved its structure by NMR spectroscopy. SURP2 exhibits a fold of the α1-α2-3₁₀-α3 topology, and the SF3a60 fragment forms an amphipathic α helix intimately contacting α1 of SURP2. We also solved the SURP1 structure, which has the same fold as SURP2. The protein-binding interface of SURP2 is quite similar to the corresponding surface of SURP1, except for two amino acid residues. One of them, Leu169, is characteristic of SF3a120 SURP2 among SURP domains. Mutagenesis showed that this single Leu residue is the critical determinant for complex formation, which reveals the protein recognition mechanism in the subunit assembly.
Functional endothelin ET<inf>B</inf> receptors are selectively expressed in human oligodendrogliomas
2005, Molecular Brain Research
Endothelin-1 (ET-1), a vasoactive and mitogenic peptide mainly produced by vascular endothelial cells, may be involved in the progression of several human tumors. Here, we present an immunohistochemical analysis of the expression pattern of ET-1 receptor subtypes (ET_A-R and ET_B-R) and a functional study of their potential role in human oligodendrogliomas and oligoastrocytomas. By comparison, we assessed the corresponding expression patterns of glioblastomas. Interestingly, a nuclear localization of ET-1 receptor subtypes (associated or not with a cytoplasmic labeling) was constantly observed in tumor cells from all three glioma types. Moreover, we noted a distinct receptor distribution in the different gliomas: a nuclear expression of ET_B-R by tumor cells was found to be restricted to oligodendrogliomas and oligoastrocytomas, while a nuclear expression of ET_A-R was only detected in tumor cells from some glioblastomas. Using primary cultures of oligodendroglial tumor cells, we confirmed the selective expression of nuclear ET_B-R, together with a plasma membrane expression, and further demonstrated that this receptor was functionally coupled to intracellular signaling pathways known to be involved in cell survival and/or proliferation: extracellular signal-regulated kinase and focal adhesion kinase activation, actin cytoskeleton reorganization. In addition, impairment of ET_B-R activation in these cells by in vitro treatment with an ET_B-R-specific antagonist induced cell death. These data point to ET-1 as a possible survival factor for oligodendrogliomas via ET_B-R activation and suggest that ET_B-R-specific antagonists might constitute a potential therapeutic alternative for oligodendrogliomas.
Endothelin receptors in lower esophageal sphincter circular smooth muscle
2005, Regulatory Peptides
To characterize endothelin (ET) receptors in the lower esophageal sphincter, we measured contraction of transverse strips from the guinea-pig lower esophageal sphincter induced by ET-related peptides and binding of ¹²⁵I-ET-1 to cell membranes prepared from the lower esophageal sphincter circular muscle. Visualization of ¹²⁵I-ET-1 binding sites in tissue was performed by autoradiography. ET-1 or ET-2 alone did not cause contraction or relaxation in resting strips. However, in carbachol precontracted lower esophageal sphincter strips, ET-1 and ET-2 caused marked, tetrodotoxin-insensitive relaxation. The ET-1-induced relaxation was abolished by BQ-123, an ET_A receptor selective antagonist, but not inhibited by BQ-788, an ET_B receptor selective antagonist. ET-3 and sarafotoxin S6c, a selective ET_B receptor agonist, did not cause relaxation in the carbachol precontracted muscle strips. These clearly indicate that ET_A receptors mediate relaxation. On the other hand, ET-3 and sarafotoxin S6c caused tetrodotoxin and atropine-insensitive contraction in the resting strips. The sarafotoxin S6c-induced contraction was inhibited by BQ-788, but not by BQ-123. Furthermore, ET-1 and ET-2 caused contraction of the resting muscle strips after pretreatment with BQ-123. This ET-1-induced contraction was also inhibited by BQ-788. Taken together, these indicate that ET_B receptors mediate contraction. Autoradiography localized ¹²⁵I-ET-1 binding to the lower esophageal sphincter circular muscle as well as longitudinal muscle of the esophagus. Binding of ¹²⁵I-ET-1 to cell membranes prepared from the circular smooth muscle was saturable and specific. Analysis of dose–inhibition curves indicated the presence of two classes of receptors, ET_A and ET_B receptors. These results demonstrate that the guinea-pig lower esophageal sphincter possesses ET_A receptors mediating relaxation and ET_B receptors mediating contraction.
Endothelin causes contraction of human esophageal muscularis mucosae through interaction with both ET<inf>A</inf> and ET<inf>B</inf> receptors
2004, Regulatory Peptides
Endothelin (ET) causes contraction of the muscularis mucosae in the guinea pig esophagus, but its role in the human esophagus remains unknown. To investigate effects of ET in the human esophagus, we measured contraction of isolated human esophageal muscularis mucosae strips caused by ET related peptides and binding of ¹²⁵I-ET-1 to cell membranes prepared from the human esophageal muscularis mucosae. Autoradiography demonstrated specific binding of ¹²⁵I-ET-1 to the muscularis mucosae and muscularis propria (muscularis externa) of the human esophagus. ET-1 caused tetrodotoxin and atropine-insensitive contraction of muscularis mucosae strips. In terms of the maximal tension of contraction, ET-1 and ET-2 were equal in efficacy. The relative potencies for ET related peptides to cause contraction were ET-1=ET-2>ET-3>sarafotoxin S6c (SX6c), an ET_B receptor agonist. ET-1 caused contraction was mildly inhibited by BQ-123, an ET_A receptor antagonist, and not by BQ-788, an ET_B receptor antagonist. It was moderately inhibited by the combination of both antagonists, indicating synergistic inhibition. Furthermore, desensitization to SX6c with SX6c pretreatment failed to abolish the contractile response to ET-1, which was completely inhibited by BQ-123. These indicate the involvement of both ET_A and ET_B receptors in the contraction. Binding of ¹²⁵I-ET-1 to cell membranes of the muscularis mucosae was saturable and specific. Analysis of dose–inhibition curves demonstrated the presence of ET_A and ET_B receptors. This study demonstrates that, the muscularis mucosae of the human esophagus, similar to that of the guinea pig esophagus, possesses both ET_A and ET_B receptors mediating muscle contraction.

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Trends in Pharmacological Sciences

ReviewsThe current endothelin receptor classification: time for reconsideration?

Abstract

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Mol. Pharmacol.

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Mol. Pharmacol.

Am. J. Physiol.

J. Pharmacol. Exp. Ther.

Br. J. Pharmacol.

Differences in endothelin receptor types in the vasculature of Bothrops jararaca (Viperidae) and Oxyrhopus guibei (Colubridae) snakes

Correlation between vascular responsivensss and expression of novel transcripts of the ET<inf>A</inf>-receptor in human vascular tissue

Solution Structures of the SURP Domains and the Subunit-Assembly Mechanism within the Splicing Factor SF3a Complex in 17S U2 snRNP

Functional endothelin ET<inf>B</inf> receptors are selectively expressed in human oligodendrogliomas

Endothelin receptors in lower esophageal sphincter circular smooth muscle

Endothelin causes contraction of human esophageal muscularis mucosae through interaction with both ET<inf>A</inf> and ET<inf>B</inf> receptors

Reviews
The current endothelin receptor classification: time for reconsideration?