Sphingosine-1-Phosphate Signaling via the EDG-1 Family of G-Protein-Coupled Receptors

2006 ◽  
Vol 905 (1) ◽  
pp. 16-24 ◽  
Author(s):  
TIMOTHY HLA ◽  
MENQ-JER LEE ◽  
NICOLAS ANCELLIN ◽  
SHOBHA THANGADA ◽  
CATHERINE H. LIU ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

scholarly journals Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1

1998 ◽  
Vol 330 (2) ◽  
pp. 605-609 ◽  
Author(s):  
C. M. Gerben ZONDAG ◽  
R. Friso POSTMA ◽  
Ingrid VAN ETTEN ◽  
Ingrid VERLAAN ◽  
H. Wouter MOOLENAAR
Keyword(s):  
Adenylate Cyclase ◽  
Map Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Lpa Receptor ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are structurally related lipid mediators that act on distinct G-protein-coupled receptors to evoke similar responses, including Ca2+ mobilization, adenylate cyclase inhibition, and mitogen-activated protein (MAP) kinase activation. However, little is still known about the respective receptors. A recently cloned putative LPA receptor (Vzg-1/Edg-2) is similar to an orphan Gi-coupled receptor termed Edg-1. Here we show that expression of Edg-1 in Sf9 and COS-7 cells results in inhibition of adenylate cyclase and activation of MAP kinase (Gi-mediated), but not Ca2+ mobilization, in response to S1P. These responses are specific in that (i) S1P action is not mimicked by LPA, and (ii) Vzg-1/Edg-2 cannot substitute for Edg-1. Thus the Edg-1 receptor is capable of mediating a subset of the cellular responses to S1P.

Sphingosine 1-Phosphate (S1P) Induces Migration and ERK/MAP-Kinase-Dependent Proliferation in Chronic Lymphocytic Leukemia (B-CLL) Due to Expression of the G Protein-Coupled Receptors S1P1/4.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4996-4996
Author(s):  
Gabriele Seitz ◽  
Sedat Yildirim ◽  
Andreas M. Boehmler ◽  
Lothar Kanz ◽  
Robert Möhle
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
G Protein ◽  
Cell Lines ◽  
Peripheral Blood ◽  
G Protein Coupled Receptors ◽  
Lymphocytic Leukemia ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Abstract Egress of lymphocytes from lymphoid organs into the circulation has been shown to depend on the presence of the lipid mediator sphingosine 1-phosphate (S1P) in the peripheral blood, and expression of corresponding S1P receptors (i.e., S1P1), that belong to the family of 7-transmembrane G protein-coupled receptors (GPCR). As circulating lymphocytic lymphoma cells are a hallmark of chronic lymphocytic leukemia, we analyzed expression of different S1P receptors and the effects of S1P on B-CLL cells. By qualitative and quantitative (TaqMan) RT-PCR, significant mRNA expression of S1P1 and S1P4 was found in CLL cell lines (EHEB, MEC-1) and in most samples (S1P1 in 88%, S1P4 in 100%) of primary CD19+ cells isolated from the peripheral blood of untreated B-CLL patients. mRNA of other S1P receptors (S1P2, S1P3, S1P5) was less consistently detected. Normal, nonmalignant B cells were strongly positive for S1P1, while other S1P receptors were weakly expressed or negative. S1P induced typical effects of chemotactic GPCR, such as actin polymerization (analyzed by flow cytometry) and chemotaxis (measured in a modified Boyden chamber assay) in CLL cell lines and primary B-CLL cells. After serum deprivation in vitro, S1P induced phosphorylation of ERK/MAP-kinase as analyzed by Western blot, demonstrating that S1P receptors expressed in CLL were able to activate signaling pathways of GPCR not only related to cell migration and chemotaxis, but also to cell proliferation. Of note, the S1P1 ligand FTY720, which induces receptor internalization after prolonged exposure and acts as an antagonist, resulted in apoptosis in CLL cell lines and primary CLL cells in vitro, as measured by MTT-test and staining with Annexin-FITC, respectively. We conclude that sphingosine 1-phosphate, which is present in the peripheral blood in considerable amounts, contributes to the trafficking of B-CLL cells expressing the GPCRs S1P1/4, and to their prolonged survival.

Sphingosine-1-Phosphate Via Activation of a G-Protein-Coupled Receptor(s) Enhances the Excitability of Rat Sensory Neurons

2006 ◽  
Vol 96 (3) ◽  
pp. 1042-1052 ◽  
Author(s):  
Y. H. Zhang ◽  
J. C. Fehrenbacher ◽  
M. R. Vasko ◽  
G. D. Nicol
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Small Diameter ◽  
G Protein Coupled Receptors ◽  
External Application ◽  
Nociceptive Neurons ◽  
Firing Threshold ◽  
Current Ramp ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Sphingosine-1-phosphate (S1P) is released by immune cells and is thought to play a key role in chemotaxis and the onset of the inflammatory response. The question remains whether this lipid mediator also contributes to the enhanced sensitivity of nociceptive neurons that is associated with inflammation. Therefore we examined whether S1P alters the excitability of small diameter, capsaicin-sensitive sensory neurons by measuring action potential (AP) firing and two of the membrane currents critical in regulating the properties of the AP. External application of S1P augments the number of APs evoked by a depolarizing current ramp. The enhanced firing is associated with a decrease in the rheobase and an increase in the resistance at firing threshold although neither the firing threshold nor the resting membrane potential are changed. Treatment with S1P enhanced the tetrodotoxin-resistant sodium current and decreased the total outward potassium current ( IK). When sensory neurons were internally perfused with GDP-β-S, a blocker of G protein activation, the S1P-induced increase in APs was completely blocked and suggests the excitatory actions of S1P are mediated through G-protein-coupled receptors called endothelial differentiation gene or S1PR. In contrast, internal perfusion with GDP-β-S and S1P increased the number of APs evoked by the current ramp. These results and our finding that the mRNAs for S1PRs are expressed in both the intact dorsal root ganglion and cultures of adult sensory neurons supports the notion that S1P acts on S1PRs linked to G proteins. Together these findings demonstrate that S1P can regulate the excitability of small diameter sensory neurons by acting as an external paracrine-type ligand through activation of G-protein-coupled receptors and thus may contribute to the hypersensitivity during inflammation.

scholarly journals Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor

2012 ◽  
Vol 108 (5) ◽  
pp. 1473-1483 ◽  
Author(s):  
Chao Li ◽  
Xian Xuan Chi ◽  
Wenrui Xie ◽  
J. A. Strong ◽  
J.-M. Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Neuronal Excitability ◽  
Small Diameter ◽  
G Protein Coupled Receptors ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Previously we demonstrated that sphingosine 1-phosphate receptor 1 (S1PR1) played a prominent, but not exclusive, role in enhancing the excitability of small-diameter sensory neurons, suggesting that other S1PRs can modulate neuronal excitability. To examine the potential role of S1PR2 in regulating neuronal excitability we used the established selective antagonist of S1PR2, JTE-013. Here we report that exposure to JTE-013 alone produced a significant increase in excitability in a time- and concentration-dependent manner in 70–80% of recorded neurons. Internal perfusion of sensory neurons with guanosine 5′- O-(2-thiodiphosphate) (GDP-β-S) via the recording pipette inhibited the sensitization produced by JTE-013 as well as prostaglandin E2. Pretreatment with pertussis toxin or the selective S1PR1 antagonist W146 blocked the sensitization produced by JTE-013. These results indicate that JTE-013 might act as an agonist at other G protein-coupled receptors. In neurons that were sensitized by JTE-013, single-cell RT-PCR studies demonstrated that these neurons did not express the mRNA for S1PR2. In behavioral studies, injection of JTE-013 into the rat's hindpaw produced a significant increase in the mechanical sensitivity in the ipsilateral, but not contralateral, paw. Injection of JTE-013 did not affect the withdrawal latency to thermal stimulation. Thus JTE-013 augments neuronal excitability independently of S1PR2 by unknown mechanisms that may involve activation of other G protein-coupled receptors such as S1PR1. Clearly, further studies are warranted to establish the causal nature of this increased sensitivity, and future studies of neuronal function using JTE-013 should be interpreted with caution.

scholarly journals Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2988
Author(s):  
Zhen Zeng ◽  
Chunxiang Ma ◽  
Kexin Chen ◽  
Mingshan Jiang ◽  
Reshma Vasu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Angiotensin Ii Receptors ◽  
Biological Processes ◽  
Substantial Evidence ◽  
Sphingosine 1 Phosphate ◽  
Gi Cancers ◽  
G Protein Coupled ◽  
Made In

It is well established that gastrointestinal (GI) cancers are common and devastating diseases around the world. Despite the significant progress that has been made in the treatment of GI cancers, the mortality rates remain high, indicating a real need to explore the complex pathogenesis and develop more effective therapeutics for GI cancers. G protein-coupled receptors (GPCRs) are critical signaling molecules involved in various biological processes including cell growth, proliferation, and death, as well as immune responses and inflammation regulation. Substantial evidence has demonstrated crucial roles of GPCRs in the development of GI cancers, which provided an impetus for further research regarding the pathophysiological mechanisms and drug discovery of GI cancers. In this review, we mainly discuss the roles of sphingosine 1-phosphate receptors (S1PRs), angiotensin II receptors, estrogen-related GPCRs, and some other important GPCRs in the development of colorectal, gastric, and esophageal cancer, and explore the potential of GPCRs as therapeutic targets.

scholarly journals Comparative Analysis of Functional Assays for Characterization of Agonist Ligands at G Protein-Coupled Receptors

2003 ◽  
Vol 8 (5) ◽  
pp. 500-510 ◽  
Author(s):  
Anke Niedernberg ◽  
Sorin Tunaru ◽  
Andree Blaukat ◽  
Bruce Harris ◽  
Evi Kostenis
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
A Priori ◽  
G Protein Coupled Receptors ◽  
Binding Assays ◽  
Functional Assays ◽  
Gtpγs Binding ◽  
Sphingosine 1 Phosphate ◽  
Intracellular Ca ◽  
G Protein Coupled

A variety of functional assays are available for agonist or antagonist screening of G protein-coupled receptors (GPCRs), but it is a priori not predictable which assay is the most suitable to identify agonists or antagonists of GPCRs with therapeutic value in humans. More specifically, it is not known how a given set of GPCR agonists compares in different functional assays with respect to potency and efficacy and whether the level of the signaling cascade that is analyzed has any impact on the detection of agonistic responses. To address this question, the authors used the recently cloned human S1P5 receptor as a model and compared a set of 3 lipid ligands (sphingosine 1-phosphate [S1P], dihydro sphingosine 1-phosphate [dhS1P], and sphingosine) in 5 different functional assays: GTPγS binding, inhibition of adenylyl cyclase activity, mobilization of intracellular Ca2+ via the FLIPR and aequorin technology, and MAP kinase (ERK1/2) activation. S1P induced agonistic responses in all except the ERK1/2 assays with EC50 values varying by a factor of 10. Whereas dhS1P was identified as a partial agonist in the GTPγS assay, it behaved as a full agonist in all other settings. Sphingosine displayed partial agonistic activity exclusively in GTPγS binding assays. The findings suggest that assays in a given cellular background may vary significantly with respect to suitability for agonist finding and that ligands producing a response may not readily be detectable in all agonist assays. ( Journal of Biomolecular Screening 2003:500-510)

scholarly journals Gα12/Gα13 Deficiency Causes Localized Overmigration of Neurons in the Developing Cerebral and Cerebellar Cortices

2007 ◽  
Vol 28 (5) ◽  
pp. 1480-1488 ◽  
Author(s):  
Alexandra Moers ◽  
Alexander Nürnberg ◽  
Sandra Goebbels ◽  
Nina Wettschureck ◽  
Stefan Offermanns
Keyword(s):  
G Protein ◽  
Purkinje Cells ◽  
Cortical Neurons ◽  
Radial Glia ◽  
G Protein Coupled Receptors ◽  
Cortical Plate ◽  
Genes Encoding ◽  
Sphingosine 1 Phosphate ◽  
Cerebellar Purkinje Cells ◽  
G Protein Coupled

ABSTRACT The heterotrimeric G proteins G12 and G13 link G-protein-coupled receptors to the regulation of the actin cytoskeleton and the induction of actomyosin-based cellular contractility. Here we show that conditional ablation of the genes encoding the α-subunits of G12 and G13 in the nervous system results in neuronal ectopia of the cerebral and cerebellar cortices due to overmigration of cortical plate neurons and cerebellar Purkinje cells, respectively. The organization of the radial glia and the basal lamina was not disturbed, and the Cajal-Retzius cell layer had formed normally in mutant mice. Embryonic cortical neurons lacking G12/G13 were unable to retract their neurites in response to lysophosphatidic acid and sphingosine-1-phosphate, indicating that they had lost the ability to respond to repulsive mediators acting via G-protein-coupled receptors. Our data indicate that G12/G13-coupled receptors mediate stop signals and are required for the proper positioning of migrating cortical plate neurons and Purkinje cells during development.

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