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Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes
Author(s) -
Healy Luke M,
Sheridan Graham K,
Pritchard Adam J,
Rutkowska Aleksandra,
Mullershausen Florian,
Dev Kumlesh K
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12207
Subject(s) - signalling , microbiology and biotechnology , receptor , internalization , signal transduction , biology , phosphorylation , antagonism , stimulation , astrocyte , chemistry , endocrinology , biochemistry , central nervous system
Background and Purpose The sphingosine 1‐phosphate receptor subtype 1 ( S1P1R ) is modulated by phosphorylated FTY720 ( p FTY720 ), which causes S1P1R internalization preventing lymphocyte migration thus limiting autoimmune response. Studies indicate that internalized S1P1R s continue to signal, maintaining an inhibition of cAMP , thus raising question whether the effects of p FTY720 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 Ca 2+ 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 p FTY720 induced long‐lasting S1P1R redistribution and continued cAMP signalling in rat astrocytes. In contrast, p FTY720 induced a transient increase of Ca 2+ in astrocytes and subsequent antagonism of Ca 2+ signalling. Notably, while leaving pFTY720 ‐induced cAMP signalling intact, the novel MNP301 peptide attenuated S1P1R ‐mediated Ca 2+ and pERK signalling in cultured rat astrocytes. Conclusions and Implications These findings suggested that p FTY720 causes continued cAMP signalling that is not dependent on S1P1R redistribution and induces functional antagonism of Ca 2+ signalling after transient stimulation. To our knowledge, this is the first report demonstrating that p FTY720 causes continued signalling in one pathway ( cAMP ) versus functional antagonism of another pathway ( Ca 2+ ) and which also suggests that redistributed S1P1R s may have differing signalling properties from those expressed at the surface.