title: Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors.
abstract: Sphingosine-1-phosphate (S1P) receptors are widely expressed in the central nervous system where they are thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum of S1P receptors and the parent compound is currently in phase III clinical trials for the treatment of multiple sclerosis. Here, we aimed to identify which cell type(s) and S1P receptor(s) of the central nervous system are targeted by FTY720P. Using calcium imaging in mixed cultures from embryonic rat cortex we show that astrocytes are the major cell type responsive to FTY720P in this assay. In enriched astrocyte cultures, we detect expression of S1P1 and S1P3 receptors and demonstrate that FTY720P activates Gi protein-mediated signaling cascades. We also show that FTY720P as well as the S1P1-selective agonist SEW2871 stimulate astrocyte migration. The data indicate that FTY720P exerts its effects on astrocytes predominantly via the activation of S1P1 receptors, whereas S1P signals through both S1P1 and S1P3 receptors. We suggest that this distinct pharmacological profile of FTY720P, compared with S1P, could play a role in the therapeutic effects of FTY720 in multiple sclerosis.
authors.affiliation: Department of G Protein-Coupled Receptors, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Mullershausen
authors.forename: Luis M
authors.initials: LM
authors.lastname: Craveiro
authors.forename: Youngah
authors.initials: Y
authors.lastname: Shin
authors.forename: Marta
authors.initials: M
authors.lastname: Cortes-Cros
authors.forename: Frederic
authors.initials: F
authors.lastname: Bassilana
authors.forename: Maribel
authors.initials: M
authors.lastname: Osinde
authors.forename: William L
authors.initials: WL
authors.lastname: Wishart
authors.forename: Danilo
authors.initials: D
authors.lastname: Guerini
authors.forename: Michaela
authors.initials: M
authors.lastname: Thallmair
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sivasankaran
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Kumlesh K
authors.initials: KK
authors.lastname: Dev
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D000068876:Fingolimod Hydrochloride; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C517408:AUY 954; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D007295:Inositol Phosphates; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D015091:beta-Alanine; D018698:Glutamic Acid; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine