<i>The astrocytic endothelin system: toward solving a mystery</i>  Focus on “Distinct pharmacological properties of ET-1 and ET-3  on astroglial gap junctions and Ca<sup>2+</sup>signaling”

Ehrenreich, Hannelore

doi:10.1152/ajpcell.1999.277.4.c614

Cited by 18 publications

(15 citation statements)

References 23 publications

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“…Atypical endothelin receptor ligand binding properties have been demonstrated in a number of cell types coexpressing ET A and ET B receptors (11,16,21). Further investigation in cell culture using coimmunoprecipitation and fluorescence resonance energy transfer techniques have demonstrated that endothelin receptors form ET A /ET B heterodimers (12,14).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

Stauffer

Westby

Greiner

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Stauffer BL, Westby CM, Greiner JJ, Van Guilder GP, DeSouza CA. Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults. Am J Physiol Regul Integr Comp Physiol 298: R261-R265, 2010. First published November 25, 2009 doi:10.1152/ajpregu.00626.2009.-The prevalence of cardiovascular disease is lower in middle-aged and older women than men. Increased endothelin-1-mediated vasoconstriction has been linked to the etiology of a number of cardiovascular diseases, including atherosclerosis, heart failure, and hypertension. It is unknown whether a sex difference in endothelin-1-mediated vasoconstrictor tone exists in middle-aged and older adults. Therefore, we tested the hypothesis that middle-aged and older men would demonstrate greater ET-1-mediated vasoconstrictor tone than age-matched women. Forearm blood flow in response to intra-arterial infusions of endothelin (ET)-1, BQ-123 (a selective ET A receptor antagonist), and BQ-788 (a selective ETB receptor antagonist) was assessed by venous occlusion plethysmography in 21 women (age: 58 Ϯ 1 yr; body mass index: 26.0 Ϯ 1.0 kg/m 2 ) and 25 men (age: 57 Ϯ 2 yr; body mass index: 26.8 Ϯ 0.7 kg/m 2 ). In response to BQ-123, the increase in forearm blood flow from baseline was significantly higher in the men than the women (24 Ϯ 5% vs. 9 Ϯ 5%; P Ͻ 0.05). In contrast, the increase in forearm blood flow in response to BQ-123 coinfused with BQ-788 was greater in the women than the men, such that the maximum vasodilation to dual endothelin receptor blockade was similar between men and women (ϳ25%). There was no difference in the vasoconstrictor response to ET-1 between the sexes. These results indicate that middle-aged and older men are under greater ET A receptor-mediated vasoconstrictor tone than age-matched women. Since the ET A receptor is the predominant receptor subtype in the coronary vasculature, this sex difference in vasoconstrictor tone may be a mechanism contributing to the sex difference in the prevalence of coronary heart disease in middle-aged and older adults.endothelin-1; endothelin receptor antagonist; endothelium; vascular function; sex differences ENDOTHELIN-1 (ET-1) IS THE most abundant and important vasoconstrictor molecule released from the vasculature. Produced by the endothelium, ET-1 is predominantly released abluminally to activate ET A and ET B receptors located on the vascular smooth muscle causing smooth muscle contraction, cell proliferation, and hypertrophy (35). ET B receptors on the vascular endothelium produce vasodilation via a nitric oxide mechanism and are also a prominent clearance mechanism for circulating ET-1. ET A receptors are the predominant subtype [10 times greater number than ET B (37)] in the arterial system and the coronary arteries, in particular (30, 31, 34). Because of this disparity in receptor number, the contribution of the ET B receptor to coronary vasoregulation is limited (25). Importantly, ET-1 expression is elevated in atherosclerotic vessels (18,32), and ET-1-mediated vasoconstrict...

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Section: Discussionmentioning

confidence: 99%

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

Stauffer

Westby

Greiner

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Recent studies suggest that ET-1 binds simultaneously to both an ET A and ET B receptor (2,11). This heterodimerization between two fully functional G protein-coupled receptors is suggested to result in a new receptor/ligand binding complex with functional properties different from those of either receptor alone (21).…”

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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“…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).…”

Section: Endothelin-1 (Et-1) Is a Potent Vasoactive Peptide That Actsmentioning

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

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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-

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The astrocytic endothelin system: toward solving a mystery Focus on “Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca²⁺signaling”

Cited by 18 publications

References 23 publications

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

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

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

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The astrocytic endothelin system: toward solving a mystery Focus on “Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca2+signaling”

Cited by 18 publications

References 23 publications

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

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

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

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The astrocytic endothelin system: toward solving a mystery Focus on “Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca²⁺signaling”