Regulation and Intracellular Trafficking Pathways of the Endothelin Receptors

Bremnes, Toril; Paasche, Joachim D.; Mehlum, Anja; Sandberg, Cecilie; Bremnes, Bjørn; Attramadal, Håvard

doi:10.1074/jbc.m000142200

Cited by 223 publications

(202 citation statements)

References 56 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…In heterologous expression systems, ETA localize primarily to the plasma membrane [4], internalize in a ligand-dependent manner [58], and then follow a recycling pathway through the pericentriolar recycling compartment and then back to the plasma membrane [5]. In contrast, ETB internalizes constitutively, without a requirement for ligand binding, and then translocates to the lysosomes for degradation [5,40].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, ETB internalizes constitutively, without a requirement for ligand binding, and then translocates to the lysosomes for degradation [5,40]. The fate of each receptor subtype is under the control of specific elements regulating protein trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…In heterologous expression systems, ETA and ETB differ in their internalization and intracellular trafficking. ETA shows ligand-dependent endocytosis and is recycled back to the plasma membrane whereas ETB internalizes constitutively and translocate to lysosomes [4][5][6]. Thus, it has been proposed that ETA, the prevalent receptor subtype in the cardiac tissue, mediates the main cellular functions of endothelin, whereas ETB is involved in the clearance of ET-1.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Merlen¹,

Farhat²,

Luo³

et al. 2013

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca 2+ signalling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei. Furthermore, in both cardiac myocytes and aortic endothelial cells, endocytosed ET:ETB complexes translocated to lysosomes and not the nuclear envelope. Although ETA and ETB can form heterodimers, the presence or absence of ETA did not alter ETB trafficking. Treatment of isolated nuclei with * Abbreviations: The abbreviations used are: 2-APB, 2-aminoethoxydiphenyl borate; A, Angiotensin II; αAR, α-adrenergic receptor;[Ca 2+ ] n , nucleoplasmic free calcium concentration; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; DMNB, 4,5-dimethoxynitrobenzyl group; DNA, deoxyribonucleic acid; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DTT, dithiothreitol; ECE1-a, endothelin converting enzyme 1a; cET-1, caged ET-1; caged ET-1, [Trp-ODMNB 21 ]ET-1; ET-1, endothelin 1; ET-2, endothelin 2; ET-3, endothelin 3; ETA, endothelin type A receptor; ETB, endothelin type B receptor; ETR, endothelin receptor; GPCR, G protein-coupled receptor; HDAC5; histone deacetylase 5; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate receptor; ISO, isoproterenol; MEF2, myocyte enhancing factor-2; PBS, phosphate buffered saline; PMSF, phenylmethanesulphonylfluoride; PNGase F, peptide N-glycosidase F; qPCR, quantitative real-time polymerase chain reaction; RNA, ribonucleic acid; RyR, ryanodine receptor; TCA, trichloroacetic acid; TFA, trifluoroacetic acid; TX-100, Triton X-100. Address correspondence to: Bruce G. Allen, Montreal Heart Institute, 5000 Belanger St,. Montréal, Québec, Canada, H1T 1C8., Telephone: (514) ] n whereas extracellular application of ETA and ETB receptor antagonists did not. These data suggest that 1) the endothelin receptor in the cardiac nuclear membranes is ETB, 2) ETB traffic directly to the nuclear membrane after biosynthesis, 3) exogenous endothelins are not ligands for ETB on nuclear membranes, and 4) ETB associated with the nuclear membranes regulate nuclear Ca 2+ signalling.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Merlen¹,

Farhat²,

Luo³

et al. 2013

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…In the ET-1-bound heterodimer, transport signals may be exposed that promote recycling to the cell surface, similar to the trafficking of the ET A receptor when expressed individually (9). In contrast, BQ3020 may expose transport motifs, which direct the ET B receptor into late endosomal/lysosomal compartments, similar as the ET B receptor when expressed alone (9,10). During intracellular trafficking the ET A receptor may dissociate from the ET B receptor, e.g.…”

Section: Heterodimerization Results In a Decreased Rate Of Et-1-mediamentioning

confidence: 99%

“…The ET A receptor internalizes in clathrin-dependent and -independent fashions and recycles to the plasma membrane (8). In contrast, the ET B receptor internalizes via a clathrin-dependent pathway and does not recycle, but is targeted to late endosomes/ lysosomes leading to down-regulation (9,10). To analyze the agonist-mediated sequestration of heterodimers, we performed ELISA experiments with cell clones expressing the ET B flag⅐YFP receptor individually or in combination with the ET A myc⅐CFP receptor.…”

Section: Heterodimerization Results In a Decreased Rate Of Et-1-mediamentioning

confidence: 99%

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Gregan

Jürgensen

Papsdorf

et al. 2004

Journal of Biological Chemistry

117

106

View full text Add to dashboard Cite

Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on endothelin A (ETEndothelins (ET-1, ET-2, and ET-3) 1 are important regulators in the vascular system. They act via two receptors: the endothelin A (ET A ) and endothelin B (ET B ) receptors (1, 2). Although human ET A and ET B receptors share 59% amino acid sequence identity (exceeding 75% at the cytoplasmic face), both receptor subtypes couple to different G proteins and differ in their ligand-induced internalization and intracellular trafficking. Whereas the ET A receptor stimulates G proteins of the G q/11 and G 12/13 families, the ET B receptor activates mainly G proteins of the G i and G q/11 families (3, 4). Whether ET B receptors also stimulate proteins of the G 12/13 family is still controversial and may depend on expression levels or cell types investigated (5, 6). Upon ligand binding, both receptor subtypes are rapidly desensitized by phosphorylation through the G protein-coupled receptor kinase type 2 (7). Following internalization via caveolae and/or clathrin-coated pits, the ET A receptor is recycled back to the cell surface (8, 9). In contrast, the ET B receptor is exclusively internalized via a clathrin-dependent pathway and transported to late endosomes and lysosomes (9, 10).The ET A receptor is mainly expressed in vascular smooth muscle cells. Its activation elicits a long-lasting contraction via an increase in cytosolic Ca 2ϩ concentrations and activation of Rho proteins (11,12). The ET B receptor is predominantly expressed in endothelial cells and stimulates the release of NO and prostacyclin, thereby causing relaxation of vascular smooth muscle cells (13). In addition, ET A and ET B receptors are co-expressed in numerous cells, e.g. astrocytes, cardiomyocytes, epithelial cells of the choroid plexus and the anterior pituitary, and certain vascular smooth muscle cells (14 -16). In disease states, such as atherosclerosis and hypercholesterolemia, vascular smooth muscle cells co-express ET A and ET B receptors (17). Because atypical ligand binding was observed for cells co-expressing ET A and ET B receptors, e.g. astrocytes, epithelial cells of the anterior pituitary, or vascular smooth muscle cells, it was suggested that the two receptor subtypes form heterodimers (15,16,18). For example, in epithelial cells of the anterior pituitary, ET B receptor-selective ligands such as sarafotoxin 6c, ET-3, and IRL1620 were competitors of 125 I-ET-1 binding only in the presence of the ET A receptor-selective antagonist BQ123 (16). In astrocytes, ET A and ET B receptors cooperatively control ET-1 clearance, because only the combi-

show abstract

Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS

Rogers

Peters

Pomonis

et al. 2002

Glia

View full text Add to dashboard Cite

The ability of mammalian central nervous system (CNS) neurons to survive and/or regenerate following injury is influenced by surrounding glial cells. To identify the factors that control glial cell function following CNS injury, we have focused on the endothelin B receptor (ET(B)R), which we show is expressed by the majority of astrocytes that are immunoreactive for glial acid fibrillary protein (GFAP) in both the normal and crushed rabbit optic nerve. Optic nerve crush induces a marked increase in ET(B)R and GFAP immunoreactivity (IR) without inducing a significant increase in the number of GFAP-IR astrocytes, suggesting that the crush-induced astrogliosis is due primarily to astrocyte hypertrophy. To define the role that endothelins play in driving this astrogliosis, artificial cerebrospinal fluid (CSF), ET-1 (an ET(A)R and ET(B)R agonist), or Bosentan (a mixed ET(A)R and ET(B)R antagonist) were infused via osmotic minipumps into noninjured and crushed optic nerves for 14 days. Infusion of ET-1 induced a hypertrophy of ET(B)R/GFAP-IR astrocytes in the normal optic nerve, with no additional hypertrophy in the crushed nerve, whereas infusion of Bosentan induced a significant decrease in the hypertrophy of ET(B)R/GFAP-IR astrocytes in the crushed but not in the normal optic nerve. These data suggest that pharmacological blockade of astrocyte ET(B)R receptors following CNS injury modulates glial scar formation and may provide a more permissive substrate for neuronal survival and regeneration.

show abstract

Regulation and Intracellular Trafficking Pathways of the Endothelin Receptors

Cited by 223 publications

References 56 publications

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS

Contact Info

Product

Resources

About