Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors

Sphingosine-1-phosphate receptors (S1P1-5) are activated by the endogenous agonist S1P and are expressed in the central nervous system. In astrocytes, activation of S1P receptors leads to phosphorylation of extracellular-signal regulated kinase (ERK), a signaling cascade which plays intimate roles in cell proliferation. Fingolimod (FrY720) is in phase III clinical trials for the treatment of multiple sclerosis and its phosphory lated version (FrY720P) activates S1P receptors. We examined the effects of FTY720P on ERK phosphorylation and determined which S1P receptor subtype(s) mediated this signaling event. FrY720P augmented ERK phosphorylation in cortical cultures prepared from embryonic day 18 rat brains and was blocked by an MEK inhibitor or by pertussis toxin. Co-localisation of phosphorylated ERK occurred in glial fibrillary acidic protein (GFAP) positive astrocytes but not neurons or oligodendrocytes. Furthermore, FrY720P stimulated ERK phosphorylation in highly enriched astrocyte cultures made from postnatal day 2 rat cortices. The effects of FTY720P were mimicked by selective S1P1 receptor agonists and blocked by SIPI receptor antagonists. Collectively, these results demonstrate that FrY720P mediates ERK phosphorylation in astrocytes via the activation of S1P1 receptors. (c) 2006 Elsevier Ltd. All rights reserved.