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

Muellershausen, Florian and Zecri, Frederic and Cetin, Cihan and Billich, Andreas and Guerini, Danilo and Seuwen, Klaus (2009) Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nature Chemical Biology, 5 (6). pp. 428-434. ISSN 1552-4469

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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 14 Dec 2009 13:49
Last Modified: 31 Jan 2013 01:00
URI: https://oak.novartis.com/id/eprint/1039

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