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PMID: 19430484 Published · ppublish English Journal Article

Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors.

Nature chemical biology ·Vol. 5 ·No. 6 ·2009-06-00 ·Pages 428-34

Mullershausen F, Zecri F, Cetin C, Billich A, Guerini D, Seuwen K

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.

MeSH Terms
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
Chemicals
Propylene Glycols Receptors, Lysosphingolipid Fingolimod Hydrochloride Sphingosine Calcium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Mullershausen Florian
Developmental & Molecular Pathways and 2Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. florian.muellershausen@novartis.com
Zecri Frédéric
Cetin Cihan
Billich Andreas
Guerini Danilo
Seuwen Klaus
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Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.173
Email
florian.muellershausen@novartis.com
Published
2009-06-00
Pages
428-34
Language
English
Region
United States
NLM ID
101231976
Subset
IM
Corrections
ErratumIn
-
CommentIn
PMID: 19448604
External Links
PubMed source DOI: 10.1038/nchembio.173 View journal details
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