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Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors

Maribel Osinde1, Florian Mullershausen, Kumlesh K Dev

  • 1Department of Neuroscience, Novartis Institutes for BioMedical Research, Unit of Neurodegeneration, Novartis Pharma, WSJ-386.7.43 Lichtstrasse 35, CH-4002 Basel, Switzerland.

Neuropharmacology
|March 24, 2007
PubMed

Insights

Fingolimod (FTY720P) activates Sphingosine-1-phosphate receptor 1 (S1P1) in astrocytes, leading to extracellular-signal regulated kinase (ERK) phosphorylation. This pathway is crucial for astrocyte proliferation and may be a therapeutic target.

Area of Science:

  • Neuroscience
  • Cell Signaling
  • Pharmacology

Background:

  • Sphingosine-1-phosphate receptors (S1P1-5) are key in the central nervous system.
  • Astrocyte S1P receptor activation influences extracellular-signal regulated kinase (ERK) phosphorylation, impacting cell proliferation.
  • Fingolimod (FTY720), a multiple sclerosis therapeutic, is phosphorylated to FTY720P, an S1P receptor agonist.

Purpose of the Study:

  • To investigate the effects of FTY720P on ERK phosphorylation in astrocytes.
  • To identify the specific S1P receptor subtype mediating FTY720P-induced ERK phosphorylation.

Main Methods:

  • Cortical cultures from embryonic day 18 rat brains were treated with FTY720P.
  • ERK phosphorylation was assessed, and signaling pathways were inhibited using MEK inhibitor and pertussis toxin.
  • Highly enriched astrocyte cultures were used to confirm cell-specific signaling.

Main Results:

  • FTY720P significantly augmented ERK phosphorylation in cortical cultures.
  • Phosphorylated ERK co-localized with glial fibrillary acidic protein (GFAP)-positive astrocytes.
  • FTY720P-induced ERK phosphorylation was mediated exclusively by the S1P1 receptor subtype.

Conclusions:

  • FTY720P activates ERK phosphorylation in astrocytes.
  • This signaling is specifically mediated through the S1P1 receptor.
  • The findings highlight S1P1 receptor activation as a key mechanism in FTY720P's astrocyte-mediated effects.

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