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Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes

Healy, Luke M.; Sheridan, Graham K.; Pritchard, Adam J.; Rutkowska, Aleksandra; Mullershausen, Florian; Dev, Kumlesh K.


Luke M. Healy

Adam J. Pritchard

Aleksandra Rutkowska

Florian Mullershausen

Kumlesh K. Dev



Background and Purpose The sphingosine 1-phosphate receptor subtype 1 (S1P1R) is modulated by phosphorylated FTY720 (pFTY720), which causes S1P1R internalization preventing lymphocyte migration thus limiting autoimmune response. Studies indicate that internalized S1P1Rs continue to signal, maintaining an inhibition of cAMP, thus raising question whether the effects of pFTY720 are due to transient initial agonism, functional antagonism and/or continued signalling. To further investigate this, the current study first determined if continued S1P1R activation is pathway specific. Experimental Approach Using human and rat astrocyte cultures, the effects of S1P1R activation on cAMP, pERK and Ca2+ signalling was investigated. In addition, to examine the role of S1P1R redistribution on these events, a novel biologic (MNP301) that prevented pFTY720-mediated S1P1R redistribution was engineered. Key Results The data showed that pFTY720 induced long-lasting S1P1R redistribution and continued cAMP signalling in rat astrocytes. In contrast, pFTY720 induced a transient increase of Ca2+ in astrocytes and subsequent antagonism of Ca2+ signalling. Notably, while leaving pFTY720-induced cAMP signalling intact, the novel MNP301 peptide attenuated S1P1R-mediated Ca2+ and pERK signalling in cultured rat astrocytes. Conclusions and Implications These findings suggested that pFTY720 causes continued cAMP signalling that is not dependent on S1P1R redistribution and induces functional antagonism of Ca2+ signalling after transient stimulation. To our knowledge, this is the first report demonstrating that pFTY720 causes continued signalling in one pathway (cAMP) versus functional antagonism of another pathway (Ca2+) and which also suggests that redistributed S1P1Rs may have differing signalling properties from those expressed at the surface. © 2013 The British Pharmacological Society.


Healy, L. M., Sheridan, G. K., Pritchard, A. J., Rutkowska, A., Mullershausen, F., & Dev, K. K. (2013). Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes. British Journal of Pharmacology, 169(5), 1114-1129.

Journal Article Type Article
Acceptance Date Mar 21, 2013
Online Publication Date Apr 16, 2013
Publication Date 2013-07
Deposit Date Aug 16, 2022
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 169
Issue 5
Pages 1114-1129
Public URL
Publisher URL