Endothelin receptor subtypes and their role in transmembrane signaling mechanisms

doi:10.1016/0163-7258(95)02015-2

Pharmacology & Therapeutics

Volume 68, Issue 3, 1995, Pages 435-471

https://doi.org/10.1016/0163-7258(95)02015-2 Get rights and content

Abstract

The endothelins (ETs) are potent vasoactive peptides that appear to be involved in diverse biological actions, for example, contraction, neuromodulation, and neurotransmission, as well as in various pathophysiological conditions, such as renal and heart failure. The diversity of actiqns of ETs may be explained in terms of (1) the existence of several receptor subtypes and (2) the activation of different signal transduction pathways. This review summarizes the state of the art in this intensively studied field, with particular focus on structural aspects, receptor heterogeneity, coupling of receptors to G-proteins, and signal transduction mechanisms mediated by the activation of ET-receptors.

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Obesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described.
To determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery.
The studies were undertaken at a University Hospital.
This was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery.
At 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R² = .49, P = .01) and change in body mass index 6 months (R² = .45, P = .011) post bariatric surgery.
Our results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery.
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ETs activate phospholipase C (PLC) resulting in the cleavage of the phospholipid phosphatidylinositol 4,5-biphosphate into diacylglycerol which stimulates PKC and inositol 1,4,5-triphosphate (IP3) which binds to IP3 receptors in the smooth endoplasmic reticulum causing cytosolic calcium concentration to increase (Deacon & Knox, 2010; Jain, Olovsson, Burton, & Yung, 2012; Kato et al., 2013; Kuwaki et al., 1997; Sokolovsky, 1995a, 1995b). ETs can also stimulate phospholipase A2, which releases arachidonic acid, a precursor of eicosanoids including prostaglandins and leukotrienes and phospholipase D that catalyzes the hydrolysis of phosphatidylcholine to generate phosphatidic acid and choline (Deacon & Knox, 2010; Kuwaki et al., 1997; Robin, Chouayekh, Bole-Feysot, Leiber, & Tanfin, 2005; Sokolovsky, 1995a, 1995b). The activation of ET receptors also increases cytosolic calcium through the Na+/H+ cotransporter and the calcium voltage and/or ligand channels that induce a sustained calcium influx.
Neuronal norepinephrine (NE) uptake is a crucial step in noradrenergic neurotransmission that regulates NE concentration in the synaptic cleft. It is a key mechanism mediated by the NE transporter (NET) which takes the neurotransmitter into the presynaptic neuron terminal or the adrenal medulla chromaffin cell. The activity of NET is short and long terms modulated by phosphorylation mediated by protein kinases A, C, and G and calcium–calmodulin-dependent protein kinase, whereas the transporter availability at the cell surface is regulated by glycosylation. Several neuropeptides like angiotensins II, III, and 1–7, bradykinin, natriuretic peptides, as well as endothelins (ETs) regulate a wide variety of biological effects, including noradrenergic transmission and in particular neuronal NE uptake. Diverse reports, including studies from our laboratory, show that ETs differentially modulate the activity and expression of NET not only in normal conditions but also in diverse cardiovascular diseases such as congestive heart failure and hypertension. Current literature supports a key role for the interaction between ETs and NE in maintaining neurotransmission homeostasis and further suggests that this interaction may represent a potential therapeutic target for various diseases, particularly hypertension.
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Salt homeostasis is essential to survival, but brain mechanisms for salt-intake control have not been fully elucidated. Here, we found that the sensitivity of Na_x channels to [Na⁺]_o is dose-dependently enhanced by endothelin-3 (ET-3). Na_x channels began to open when [Na⁺]_o exceeded ∼150 mM without ET-3, but opened fully at a physiological [Na⁺]_o (135–145 mM) with 1 nM ET-3. Importantly, ET-3 was expressed in the subfornical organ (SFO) along with Na_x, and the level was robustly increased by dehydration. Pharmacological experiments revealed that endothelin receptor B (ET_BR) signaling is involved in this modulation of Na_x gating through protein kinase C and ERK1/2 activation. ET_BR agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ET_BR antagonist attenuated salt aversion during dehydration. These results indicate that ET-3 expression in the SFO is tightly coupled with body-fluid homeostasis through modulation of the [Na⁺]_o sensitivity of Na_x.
Loss of retinal capillary vasoconstrictor response to Endothelin-1 following pressure increments in living isolated rat retinas
2010, Experimental Eye Research
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The mechanisms causing loss of Et-1 response after pressure increments are presently unclear, but we can make a working hypothesis. Et-1 release has been shown to accompany acute IOP spikes (Hollo et al., 2000), and under physiological conditions, Et-1 binds irreversibly to its receptors, so that cells need to rebuild their receptor array to reinstate their full sensitivity (Sokolovsky, 1995). Indeed, Et-1 application on isolated human eyes has been shown to cause vessel desensitization to Et-1 stimulation lasting hours (Haefliger et al., 1992).
Increased intraocular pressure (IOP) is a major risk factor for glaucoma, and its contribution to neuronal damage appears multi-factorial. An open issue is whether pressure effects on blood vessels contribute to neuronal damage. In particular, little is known about pressure effects on capillaries, which are the site of most metabolic exchange in the retina, but cannot be easily visualized in vivo. To address this issue, here we have imaged retinal capillaries in acutely isolated living rat retinas, and measured alterations in capillary viability, caliber and response to vasoactive stimuli after controlled pressure stimuli. We found that capillary viability, diameter and response to vasodilator stimulation are not affected after pressure increments; yet, a prolonged lack of capillary response to the vasoconstrictor Endothelin-1 (Et-1) is observed. Considering that Et-1 is a major component of the endogenous control of retinal blood flow the present data lead to the hypothesis that prolonged or repeated IOP elevation could induce capillary disregulation contributing to neuronal damage over time.
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One of the proteins secreted by endothelial cells is endothelin (ET), which is a potent vasoconstrictor and pressor agent involved in the regulation of blood pressure. There are four isoforms of ET of which ET-1 is the best studied [79]. Receptors for ET-1 are expressed not only in smooth muscle cells but also in adipocytes and a number of other tissues.
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Endothelin-1 (ET-1) induces contraction of vascular smooth muscle through binding to endothelin type A receptor (ET_AR). COS-7 cells stably expressing high levels of the ET_AR were established (designated COS-7(ET_AR)). The COS-7(ET_AR) cell bound [¹²⁵I]ET-1 with a K_d of 932 ± 161 pM and a B_max of 74 ± 13 fmol/2 × 10⁵ cells. [¹²⁵I]ET-1 binding was inhibited by ET-1 and the ET_AR antagonist BQ-610, but not by the endothelin type B receptor (ET_BR) antagonist BQ-788. In clones expressing two ET_AR mutants containing D46N or R53Q substitutions in the first extracellular domain of the receptor, [¹²⁵I]ET-1 binding activity was dramatically reduced. This suggests that these single amino acid substitutions alter the three-dimensional structure of the ligand-binding domain of the ET_AR. Using COS-7(ET_AR) cell, we showed that Ca²⁺ or Mg²⁺ was essential for ET-1 binding to the ET_AR and that ET-1 treatment induced postreceptor signaling, that is, intracellular accumulation of cyclic AMP (cAMP) and Ca²⁺ mobilization. The COS-7(ET_AR) established in this study will be a useful tool for screening ET-1 antagonists for treating hypertension.

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Endothelin receptor subtypes and their role in transmembrane signaling mechanisms

Abstract

FEBS Lett.

FEBS Lett.

Eur. J. Pharmacol.

J. Biol. Chem.

Neurochem. Int.

Peptides

Cell

Biochem. Pharmacol.

Neurochem. Int.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol. (Mol. Pharmacol. Section)

Kidney Int.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol. (Mol. Pharmacol. Section)

FEBS Lett.

Arch. Biochem. Biophys.

J. Biol. Chem.

Trends Neurosci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Cell

Life Sci.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocrinol.

Identification of a ligand-binding site of the human endothelin A receptor and the specific region required for ligand selectivity

Eur. J. Biochem.

Peptide/protein structure analysis using chemical shift index method: upfield α-CH values reveal dynamic helices and αl sites

Biochem. Biophys. Res. Commun.

Conformational isomerism of endothelin in acidic acqueous media: a conformational NOESY analysis

Biochemistry

The fete of radiolabeled endothelin-1 and endothelin-3 in the rat

J. Cardiovasc. Pharmacol.

Cloning and expression of cDNA encoding an endothelin receptor

Nature

Mutational analysis of human endothelin receptors ETA and ETB. Identification of regions involved in the selectivity for endothelin-3 or cyclo-(DTrp-D-Asp-Pro-D-Val-Leu)

Eur. J. Biochem.

Impaired binding properties of endothelin-1 receptors in human endometrial carcinoma tissue

Cancer

Peptide/protein structure analysis using chemical shift index method: upfield α-CH values reveal dynamic helices and α_l sites

Mutational analysis of human endothelin receptors ET_A and ET_B. Identification of regions involved in the selectivity for endothelin-3 or cyclo-(DTrp-D-Asp-Pro-D-Val-Leu)