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Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo
Mari Kono, … , Ewa M. Turner, Richard L. Proia
Mari Kono, … , Ewa M. Turner, Richard L. Proia
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):2076-2086. https://doi.org/10.1172/JCI71194.
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Technical Advance Inflammation Article has an altmetric score of 22

Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo

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Abstract

Activation of the GPCR sphingosine-1-phosphate receptor 1 (S1P1) by sphingosine-1-phosphate (S1P) regulates key physiological processes. S1P1 activation also has been implicated in pathologic processes, including autoimmunity and inflammation; however, the in vivo sites of S1P1 activation under normal and disease conditions are unclear. Here, we describe the development of a mouse model that allows in vivo evaluation of S1P1 activation. These mice, known as S1P1 GFP signaling mice, produce a S1P1 fusion protein containing a transcription factor linked by a protease cleavage site at the C terminus as well as a β-arrestin/protease fusion protein. Activated S1P1 recruits the β-arrestin/protease, resulting in the release of the transcription factor, which stimulates the expression of a GFP reporter gene. Under normal conditions, S1P1 was activated in endothelial cells of lymphoid tissues and in cells in the marginal zone of the spleen, while administration of an S1P1 agonist promoted S1P1 activation in endothelial cells and hepatocytes. In S1P1 GFP signaling mice, LPS-mediated systemic inflammation activated S1P1 in endothelial cells and hepatocytes via hematopoietically derived S1P. These data demonstrate that S1P1 GFP signaling mice can be used to evaluate S1P1 activation and S1P1-active compounds in vivo. Furthermore, this strategy could be potentially applied to any GPCR to identify sites of receptor activation during normal physiology and disease.

Authors

Mari Kono, Ana E. Tucker, Jennifer Tran, Jennifer B. Bergner, Ewa M. Turner, Richard L. Proia

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Figure 4

S1P1 activation in tissues.

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S1P1 activation in tissues.
Histological sections from S1P1 GFP signalin...
Histological sections from S1P1 GFP signaling and H2B-GFP mice were stained with DAPI, and the images were captured with an inverted laser-scanning confocal microscope. Small arrowheads point to GFP+ vascular structures. The tissues of 5 mice for each genotype were examined. CA, central arteries; HEV, high endothelial venules; MS, medullary sinuses; SS, subcapsular sinuses. Scale bars: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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