Subtype-Specific Desensitization of Human Endothelin ET<sub>A</sub> and ET<sub>B</sub> Receptors Reflects Differential Receptor Phosphorylation

Cramer, Henning; Müller‐Esterl, Werner; Schröeder, C.

doi:10.1021/bi9708848

Cited by 50 publications

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“…Thus, the cytoplasmic tail of ET B may confer higher affinities of ␤-arrestin binding. Although this remains to be demonstrated, Cramer et al (22) have reported that the ET B receptor subtype is more efficiently phosphorylated than the ET A receptor subtype after agonist stimulation in transfected CHO cells. Furthermore, this finding was found to correlate with the rapid inactivation of the inositol phosphate response through the ET B receptors as compared with the more sustained activity observed through agonist-activated ET A receptors in these cells.…”

Section: Discussionmentioning

confidence: 94%

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Paasche

Attramadal

Sandberg

et al. 2001

Journal of Biological Chemistry

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We recently reported that the endothelin (ET) receptor subtypes ET 275, 17596 -17604). The ET A receptor was shown to follow the recycling route of transferrin, whereas ET B is targeted to lysosomes for degradation. In the present study we have investigated the mechanisms of ET receptor subtype-specific targeting to distinct intracellular trafficking pathways. Truncation mutants of the ET A and ET B receptors with deletions of the cytoplasmic carboxyl-terminal tail distal to the palmitoylation site were found to mediate inositol phosphate accumulation and to internalize upon agonist stimulation, although internalization occurred at a slower rate as compared with the wild-type receptors. However, the truncated ET A receptor was no longer able to undergo recycling. Rather, both truncation mutants were recognized by ␤-arrestin for recruitment to endocytosis and were sorted to lysosomes by a dynamin-dependent internalization pathway. Furthermore, studies of chimeric ET A and ET B receptors where the cytoplasmic tail of ET A was swapped with the corresponding domain of ET B , and vice versa, revealed that the cytoplasmic tail of ET B is required for efficient lysosomal sorting and that signals for targeting to recycling reside in the cytoplasmic tail of the ET A receptor.The multiple physiological effects of the vasoactive peptide endothelin (ET) 1 (1) are mediated by the G protein-coupled receptors (GPCRs) ET A and ET B (2). In the vasculature, ET A receptors residing on the smooth muscle cells mediate prolonged vasoconstriction (3), whereas ET B receptors, which are on the plasma membrane of endothelial cells, are primarily considered to cause NO-mediated vasodilatation (4). In addition, considerable evidence now also supports a role for ET B receptors in the clearance of plasma ET-1 from the circulation (5-8). In order to elucidate the molecular mechanisms of these distinct physiological responses, we recently characterized the intracellular trafficking pathways of the ET A and ET B receptors (9). Upon agonist stimulation both receptor subtypes are rapidly internalized by mechanisms that depend on G proteincoupled receptor kinase, arrestin, clathrin, and dynamin. Interestingly, the internalized ET A and ET B receptors initially appear to share a common path into Rab5-positive early endosomes. However, the two receptor subtypes are subsequently targeted to different intracellular fates. Whereas the ET A receptor follows the recycling pathway through the pericentriolar recycling compartment and reappears at the plasma membrane, the ET B receptor is directed to lysosomes for degradation. In terms of physiological effects, rapid recycling of the ET A receptor may provide the basis for reestablishment of the signaling response, and thus for the sustained vasoconstriction mediated through this receptor. Conversely, lysosomal targeting of the ET B receptor is consistent with a role for this receptor subtype in the clearance of ET-1 from the circulation. In this respect, it was recently also demonstrated that ET-1 is cotr...

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Section: Discussionmentioning

confidence: 94%

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Paasche

Attramadal

Sandberg

et al. 2001

Journal of Biological Chemistry

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“…ET A receptors are expressed abundantly on vascular smooth muscle cells (24). Two types of ET B receptors have been identified: ET B2 receptors are expressed on vascular smooth muscle cells and mediate vasoconstriction; ET B1 receptors are expressed on endothelial cells and contribute to vasodilatation at least in part through release of nitric oxide and prostacyclin (9,10,33). In the human pulmonary artery, the ET A receptors have been found to predominate in arteries from 0.5 to Ͼ8 mm in diameter, although the number of ET B receptors increases with decreasing arterial diameter (3).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Chen

Balyakina

Lawrence³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We examined the hypothesis that the potent vasoconstrictor endothelin (ET)-1 regulates both its own production and production of the vasodilator prostaglandins PGE 2 and prostacyclin in sheep peripheral lung vascular smooth muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1; expression of the prepro (pp)-ET-1, cyclooxygenase (COX)-1, and COX-2 genes was examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were measured by ELISA with and without addition of the protein synthesis inhibitor brefeldin A (50 g/ml). Prostaglandin levels were measured by gas chromatography-mass spectrometry. Through use of ET A and ETB antagonists (BQ-610 and BQ-788, respectively), the contribution of the ET receptors to COX-1 and -2 expression and ppET-1 gene expression was examined. The contribution of phosphorylated p38 and p44/42 MAPK on COX-1 and COX-2 expression was also examined with MAPK inhibitors (p38, SB-203580 and p44/ 42, PD-98056). ET-1 resulted in transient increases in ppET-1, COX-1, and COX-2 gene and protein expression and release of 6-keto-PGF1␣ and PGE2 (P Ͻ 0.05). Both internalization of ET-1 and synthesis of new peptide contributed to an increase in intracellular ET-1 (P Ͻ 0.05). Although increased ppET-1 was regulated by both ETA and ETB, COX-2 expression was upregulated only by ETA; COX-1 expression was unaffected by either antagonist. ET-1 treatment resulted in transient phosphorylation of p38 and p44/42 MAPK; inhibitors of these MAPKs suppressed expression of COX-2 but not COX-1. Our data indicate that local production of ET-1 regulates COX-2 by activation of the ETA receptor and phosphorylation of p38 and p44/42 MAPK in PLVSMC.prostacyclin; prostaglandin E2; endothelin receptors

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“…Studies in the pulmonary vasculature suggest that the actions of ET-1 are mediated by at least three receptors: one ET A receptor and two ET B receptor subtypes. Pharmacological studies in several species indicate that the endothelial ET B receptor (designated ET B1 ) mediates vasodilatation, whereas the ET B2 receptor expressed in smooth muscle acts as vasoconstrictor (5,7,9).…”

Section: Discussionmentioning

confidence: 99%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to exogenous ET-1 for 18 h revealed that only the L2 cells internalized ET-1, and internalization by hypertensive L2 cells was significantly reduced when compared with controls. Treatment with ET A (BQ-610) and ETB (BQ-788) receptor antagonists demonstrated that both receptors contributed to internalization of ET-1 in control L2 cells, whereas in hypertensive cells only when both receptor antagonists were used in combination was significant suppression of ET-1 internalization found. We conclude that in sheep receiving CAE, alterations in ET B receptors in cells of the L2 layer may contribute to the maintenance of CPH via alterations in their expression, distribution, and activity.ET A receptor; ETB receptor; smooth muscle cells; pulmonary hypertension; endothelin SINCE ITS DISCOVERY 12 YEARS AGO, endothelin (ET) has been shown to contribute to a wide variety of physiological and pathophysiological processes in various systems (22). The ET family of 21 amino acid peptides exists in three distinct isoforms: ET-1, ET-2, and ET-3. It is an extremely potent vasoconstrictor resulting in slowly developing and sustained contraction. Although the endothelial cell was originally described as the source of ET-1, it is now known that several other cell types, including pulmonary vascular smooth muscle cells, synthesize this peptide (33, 36).The biological effects of ET-1 are mediated by two distinct ET receptor subtypes, ET A and ET B (1, 35). The affinity of the ET A receptor for ET-1 has been shown to be ϳ100 times that for ET-3 (ET-1 Ͼ ET-2 Ͼ ET-3), whereas the affinity of the ET B receptor is equipotent for all three isoforms of ET (34). Early reports indicated that the ET A receptor on smooth muscle was responsible for the vasoconstrictor effect of ET-1, whereas the ET B receptor on endothelial cells modulated ET-1-induced vasodilation. However, recent pharmacological studies suggest that there are two classes of ET B with cell specific effects, ET B1 on endothelial cells mediating vasodilation and ET B2 on smooth muscle cells mediating vasoconstriction (9). The ET B receptor also functions as a "clearance receptor" and is particularly important in the lung, where 50% of ET-1 is retained (22,29).ET-1 has been linked to the development of chronic pulmonary hypertension (CPH). Increased expression of the peptide has been demonstrated in endothelial cells of pulmonary arteries from patients with idiopathic and secondary forms of pulmonary hypertension (15), and arterial-to-venous ratios of ET-1 protein were found to be elevated above the normal range in patients with pulmonary hypertension (40). Several studies have linked increased expression of ET-1 to the development of hypoxia-induced CPH in rats (5, 24), and use of ET-1 receptor antagonists has been shown both to inhibit progression of the disease and to promote recovery (4,10,43).Although these studies support a central role for ET-1 in the pathogenesis of CPH, the picture is likely more complicated than first suspected, in that prepro-ET-1 (ppET-1) mRNA is...

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Subtype-Specific Desensitization of Human Endothelin ET_A and ET_B Receptors Reflects Differential Receptor Phosphorylation

Cited by 50 publications

References 1 publication

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

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Subtype-Specific Desensitization of Human Endothelin ETA and ETB Receptors Reflects Differential Receptor Phosphorylation

Cited by 50 publications

References 1 publication

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

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Subtype-Specific Desensitization of Human Endothelin ET_A and ET_B Receptors Reflects Differential Receptor Phosphorylation