Abstract |
Targeting sphingosine-1-phosphate receptors with the oral immunomodulator drug FTY720 ( fingolimod) has demonstrated substantial efficacy in the treatment of multiple sclerosis. The drug is phosphorylated in vivo, and most of the clinical effects of FTY720-phosphate ( FTY720P) are thought to be mediated via S1P1 receptors on lymphocytes and endothelial cells, leading to sequestration of lymphocytes in secondary lymphoid organs. FTY720P was described to act as a "functional antagonist" by promoting efficient internalization of S1P1 receptors. We demonstrate here that S1P1 receptors activated by FTY720P retain signaling activity for hours in spite of a quantitative internalization. Structural analogs of FTY720P with shorter alkyl side chains retained potency and efficacy in a functional assay but failed to promote long-lasting receptor internalization and signaling. We show that persistent signaling translates into an increased chemokinetic migration of primary human umbilical vein endothelial cells, which suggests persistent agonism as a crucial parameter in the mechanism of action of FTY720.
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Authors | Florian Mullershausen, Frédéric Zecri, Cihan Cetin, Andreas Billich, Danilo Guerini, Klaus Seuwen |
Journal | Nature chemical biology
(Nat Chem Biol)
Vol. 5
Issue 6
Pg. 428-34
(Jun 2009)
ISSN: 1552-4469 [Electronic] United States |
PMID | 19430484
(Publication Type: Journal Article)
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Chemical References |
- Propylene Glycols
- Receptors, Lysosphingolipid
- Fingolimod Hydrochloride
- Sphingosine
- Calcium
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Topics |
- Animals
- CHO Cells
- Calcium
(metabolism)
- Cell Movement
- Cricetinae
- Cricetulus
- Endocytosis
- Endothelium, Vascular
(cytology, metabolism)
- Fingolimod Hydrochloride
- Humans
- Magnetic Resonance Spectroscopy
- Mass Spectrometry
- Propylene Glycols
(pharmacology)
- Receptors, Lysosphingolipid
(metabolism)
- Signal Transduction
(drug effects)
- Sphingosine
(analogs & derivatives, pharmacology)
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