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Molecular Pharmacology

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Research ArticleArticle

FTY720-P Activates Sphingosine-1-phosphate Receptor 2 and Selectively Couples to Gα12/13/ Rho/ ROCK to Induce Myofibroblast Contraction

Katrin Sobel, Lucile Monnier, Katalin Menyhart, Matthias Bolinger, Rolf Studer, Oliver Nayler and John Gatfield
Molecular Pharmacology March 11, 2015, mol.114.097261; DOI: https://doi.org/10.1124/mol.114.097261
Katrin Sobel
Actelion Pharmaceuticals Ltd
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Lucile Monnier
Actelion Pharmaceuticals Ltd
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Katalin Menyhart
Actelion Pharmaceuticals Ltd
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Matthias Bolinger
Actelion Pharmaceuticals Ltd
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Rolf Studer
Actelion Pharmaceuticals Ltd
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Oliver Nayler
Actelion Pharmaceuticals Ltd
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John Gatfield
Actelion Pharmaceuticals Ltd
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Abstract

FTY720-P is a non-selective Sphingosine-1-phosphate (S1P) receptor agonist thought to be devoid of activity at the S1P2 receptor subtype. However, we have recently shown that FTY720-P displays significant S1P2 receptor agonist activity in recombinant cells and in fibroblasts expressing endogenous S1P2 receptors. To elucidate the S1P2-dependent signaling pathways that were activated by FTY720-P, we employed second messenger assays and impedance-based assays in combination with pharmacological and siRNA-based pathway inhibition in recombinant CHO-S1P2 cells as well as human lung myofibroblasts generated in vitro. In CHO-S1P2 cells, FTY720-P did not modulate cAMP or calcium levels. However, reporter-gene assays, impedance-based assays with a selective Rho-associated kinase (ROCK) inhibitor, Gα12/13 knock-down and activated Rho-pull-down assays demonstrated that FTY720-P potently activated Gα12/13/ Rho/ ROCK signaling. S1P similarly activated Gα12/13/ Rho/ ROCK signaling via S1P2 receptors, while the two selective S1P1 receptor agonists ponesimod and SEW2871 were inactive. In lung myofibroblasts, which mainly expressed the S1P2 receptor subtype, we showed that FTY720-P selectively activated the Gα12/13/ Rho/ ROCK pathway via the S1P2 receptor. Moreover, the activation of the Gα12/13/ Rho/ ROCK pathway in myofibroblasts by FTY720-P caused potent myofibroblast contraction similar to that induced by the natural ligand S1P. Thus, complementing second messenger assays with unbiased label-free assays or with phenotypic assays in native expression systems can uncover activation of additional pathways such as Gα12/13/ Rho/ ROCK signaling.

  • Gi family
  • Gs family
  • Gq/11 family
  • G12,13;other G's
  • cAMP
  • Calcium (G Protein Coupled Signals)
  • Sphingolipids
  • G protein regulation
  • Rho
  • Imaging with fluorescent indicators (e.g. Ca2+ imaging)
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Research ArticleArticle

FTY720-P Activates Sphingosine-1-phosphate Receptor 2 and Selectively Couples to Gα12/13/ Rho/ ROCK to Induce Myofibroblast Contraction

Katrin Sobel, Lucile Monnier, Katalin Menyhart, Matthias Bolinger, Rolf Studer, Oliver Nayler and John Gatfield
Molecular Pharmacology March 11, 2015, mol.114.097261; DOI: https://doi.org/10.1124/mol.114.097261

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Research ArticleArticle

FTY720-P Activates Sphingosine-1-phosphate Receptor 2 and Selectively Couples to Gα12/13/ Rho/ ROCK to Induce Myofibroblast Contraction

Katrin Sobel, Lucile Monnier, Katalin Menyhart, Matthias Bolinger, Rolf Studer, Oliver Nayler and John Gatfield
Molecular Pharmacology March 11, 2015, mol.114.097261; DOI: https://doi.org/10.1124/mol.114.097261
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