G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3665-3667 ◽  
Author(s):  
Maria L. Allende ◽  
Tadashi Yamashita ◽  
Richard L. Proia
Keyword(s):  
Endothelial Cells ◽  
G Protein ◽  
Receptor Expression ◽  
S1p1 Receptor ◽  
Cellular Processes ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
The One ◽  
G Protein Coupled ◽  
Vascular Maturation

AbstractSphingosine-1-phosphate (S1P) stimulates signaling pathways via G-protein-coupled receptors and triggers diverse cellular processes, including growth, survival, and migration. In S1P1 receptor-deficient embryos, blood vessels were incompletely covered by vascular smooth muscle cells (VSMCs), indicating the S1P1 receptor regulates vascular maturation. Because S1P1 receptor expression is not restricted to a particular cell type, it was not known whether the S1P1 receptor controlled VSMC coverage of vessels in a cell-autonomous fashion by functioning directly in VSMCs or indirectly through its activity in endothelial cells (ECs). By using the Cre/loxP system, we disrupted the S1P1 gene solely in ECs. The phenotype of the conditional mutant embryos mimicked the one obtained in the embryos globally deficient in S1P1. Thus, vessel coverage by VSMCs is directed by the activity of the S1P1 receptor in ECs. (Blood. 2003;102:3665-3667)

Exogenous and intracellularly generated sphingosine 1-phosphate can regulate cellular processes by divergent pathways

2003 ◽  
Vol 31 (6) ◽  
pp. 1216-1219 ◽  
Author(s):  
S. Spiegel ◽  
S. Milstien
Keyword(s):  
Cell Growth ◽  
Cell Motility ◽  
G Protein Coupled Receptors ◽  
Biological Processes ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Sphingosine 1 Phosphate ◽  
Cytoskeletal Rearrangements ◽  
G Protein Coupled ◽  
Vascular Maturation

S1P (sphingosine 1-phosphate) is the ligand for a family of specific G-protein-coupled receptors that regulate a wide variety of important cellular functions, including vascular maturation, angiogenesis, cell growth, survival, cytoskeletal rearrangements and cell motility. However, S1P also may have intracellular functions. In this review, we discuss two examples that clearly indicate that intracellularly generated and exogenous S1P can regulate biological processes by divergent pathways.

scholarly journals Edg-1, the G protein–coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation

2000 ◽  
Vol 106 (8) ◽  
pp. 951-961 ◽  
Author(s):  
Yujing Liu ◽  
Ryuichi Wada ◽  
Tadashi Yamashita ◽  
Yide Mi ◽  
Chu-Xia Deng ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled ◽  
Vascular Maturation

Sphingosine-1-phosphate activates BKCachannels independently of G protein-coupled receptor in human endothelial cells

2006 ◽  
Vol 290 (4) ◽  
pp. C1000-C1008 ◽  
Author(s):  
Moon Young Kim ◽  
Guo Hua Liang ◽  
Ji Aee Kim ◽  
Young Ju Kim ◽  
Seikwan Oh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
G Protein ◽  
Channel Activity ◽  
Human Endothelial Cells ◽  
Channel Activation ◽  
Whole Cell ◽  
Bath Solution ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled ◽  
Inside Out

The effect of sphingosine-1-phosphate (S1P) on large-conductance Ca2+-activated K+(BKCa) channels was examined in primary cultured human umbilical vein endothelial cells by measuring intracellular Ca2+concentration ([Ca2+]i), whole cell membrane currents, and single-channel activity. In nystatin-perforated current-clamped cells, S1P hyperpolarized the membrane and simultaneously increased [Ca2+]i. [Ca2+]iand membrane potentials were strongly correlated. In whole cell clamped cells, BKCacurrents were activated by increasing [Ca2+]ivia cell dialysis with pipette solution, and the activated BKCacurrents were further enhanced by S1P. When [Ca2+]iwas buffered at 1 μM, the S1P concentration required to evoke half-maximal activation was 403 ± 13 nM. In inside-out patches, when S1P was included in the bath solution, S1P enhanced BKCachannel activity in a reversible manner and shifted the relationship between Ca2+concentration in the bath solution and the mean open probability to the left. In whole cell clamped cells or inside-out patches loaded with guanosine 5′- O-(2-thiodiphosphate) (GDPβS; 1 mM) using a patch pipette, GDPβS application or pretreatment of cells with pertussis toxin (100 ng/ml) for 15 h did not affect S1P-induced BKCacurrent and channel activation. These results suggest that S1P enhances BKCachannel activity by increasing Ca2+sensitivity. This channel activation hyperpolarizes the membrane and thereby increases Ca2+influx through Ca2+entry channels. Inasmuch as S1P activates BKCachannels via a mechanism independent of G protein-coupled receptors, S1P may be a component of the intracellular second messenger that is involved in Ca2+mobilization in human endothelial cells.

scholarly journals Inhibitory and Stimulatory Regulation of Rac and Cell Motility by the G12/13-Rho and Gi Pathways Integrated Downstream of a Single G Protein-Coupled Sphingosine-1-Phosphate Receptor Isoform

2003 ◽  
Vol 23 (5) ◽  
pp. 1534-1545 ◽  
Author(s):  
Naotoshi Sugimoto ◽  
Noriko Takuwa ◽  
Hiroyuki Okamoto ◽  
Sotaro Sakurada ◽  
Yoh Takuwa
Keyword(s):  
Cell Migration ◽  
G Protein ◽  
Pertussis Toxin ◽  
Kinase Inhibitors ◽  
Fiber Formation ◽  
Membrane Ruffling ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
G Protein Coupled ◽  
Stimulation Of

ABSTRACT The G protein-coupled receptors S1P2/Edg5 and S1P3/Edg3 both mediate sphingosine-1-phosphate (S1P) stimulation of Rho, yet S1P2 but not S1P3 mediates downregulation of Rac activation, membrane ruffling, and cell migration in response to chemoattractants. Specific inhibition of endogenous Gα12 and Gα13, but not of Gαq, by expression of respective C-terminal peptides abolished S1P2-mediated inhibition of Rac, membrane ruffling, and migration, as well as stimulation of Rho and stress fiber formation. Fusion receptors comprising S1P2 and either Gα12 or Gα13, but not Gαq, mediated S1P stimulation of Rho and also inhibition of Rac and migration. Overexpression of Gαi, by contrast, specifically antagonized S1P2-mediated inhibition of Rac and migration. The S1P2 actions were mimicked by expression of V14Rho and were abolished by C3 toxin and N19Rho, but not Rho kinase inhibitors. In contrast to S1P2, S1P3 mediated S1P-directed, pertussis toxin-sensitive chemotaxis and Rac activation despite concurrent stimulation of Rho via G12/13. Upon inactivation of Gi by pertussis toxin, S1P3 mediated inhibition of Rac and migration just like S1P2. These results indicate that integration of counteracting signals from the Gi- and the G12/13-Rho pathways directs either positive or negative regulation of Rac, and thus cell migration, upon activation of a single S1P receptor isoform.

scholarly journals Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jan Müller ◽  
Wolfram von Bernstorff ◽  
Claus-Dieter Heidecke ◽  
Tobias Schulze
Keyword(s):  
Cytokine Production ◽  
Receptor Expression ◽  
Biological Processes ◽  
Environmental Signals ◽  
Before And After ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
And Migration ◽  
G Protein Coupled

Introduction. Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P1–5) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods. Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results. All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P1. In contrast, M1-polarized macrophages significantly downregulated S1P4. The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion. The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.

scholarly journals The G Protein-Coupled Receptor Kinases (GRKs) in Chemokine Receptor-Mediated Immune Cell Migration: From Molecular Cues to Physiopathology

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 75
Author(s):  
Marta Laganà ◽  
Géraldine Schlecht-Louf ◽  
Françoise Bachelerie
Keyword(s):  
G Protein ◽  
Chemokine Receptor ◽  
Immune Cell ◽  
Neutrophil Migration ◽  
G Protein Coupled Receptor ◽  
Receptor Kinases ◽  
Immune Cell Migration ◽  
And Migration ◽  
G Protein Coupled ◽  
Gpcr Desensitization

Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes. The guidance cues for neutrophil migration are emphasized based on several alterations affecting GRKs or GPCRs reported to be involved in pathological conditions.

Distinct signals via Rho GTPases and Src drive shape changes by thrombin and sphingosine-1-phosphate in endothelial cells

2002 ◽  
Vol 115 (12) ◽  
pp. 2475-2484 ◽  
Author(s):  
Valérie Vouret-Craviari ◽  
Christine Bourcier ◽  
Etienne Boulter ◽  
Ellen Van Obberghen-Schilling
Keyword(s):  
Endothelial Cells ◽  
Rho Gtpases ◽  
Actin Polymerization ◽  
Morphological Changes ◽  
Umbilical Vein ◽  
Cell Spreading ◽  
Actin Binding ◽  
Sphingosine 1 Phosphate ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells

Soluble mediators such as thrombin and sphingosine-1-phosphate regulate morphological changes in endothelial cells that affect vascular permeability and new blood vessel formation. Although these ligands activate a similar set of heterotrimeric G proteins, thrombin causes cell contraction and rounding whereas sphingosine-1-phosphate induces cell spreading and migration. A functional requirement for Rho family GTPases in the cytoskeletal responses to both ligands has been established, yet the dynamics of their regulation and additional signaling mechanisms that lead to such opposite effects remain poorly understood. Using a pull-down assay to monitor the activity of Rho GTPases in human umbilical vein endothelial cells, we find significant temporal and quantitative differences in RhoA and Rac1 activation. High levels of active RhoA rapidly accumulate in cells in response to thrombin whereas Rac1 is inhibited. In contrast, sphingosine-1-phosphate addition leads to comparatively weak and delayed activation of RhoA and it activates Rac1. In addition, we show here that sphingosine-1-phosphate treatment activates a Src family kinase and triggers recruitment of the F-actin-binding protein cortactin to sites of actin polymerization at the rim of membrane ruffles. Both Src and Rac pathways are essential for lamellipodia targeting of cortactin. Further, Src plays a determinant role in sphingosine-1-phosphate-induced cell spreading and migration. Taken together these data demonstrate that the thrombin-induced contractile and immobile phenotype in endothelial cells reflects both robust RhoA activation and Rac inhibition, whereas Src- and Rac-dependent events couple sphingosine-1-phosphate receptors to the actin polymerizing machinery that drives the extension of lamellipodia and cell migration.

Identification of G protein-coupled endothelin receptors in cultured bovine endothelial cells

1991 ◽  
Vol 174 (3) ◽  
pp. 1343-1346 ◽  
Author(s):  
Satoru Eguchi ◽  
Masamichi Kozuka ◽  
Shigehisa Hirose ◽  
Teizo Ito ◽  
Yukio Hirata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
G Protein ◽  
Endothelin Receptors ◽  
Bovine Endothelial Cells ◽  
G Protein Coupled
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