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Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1p) receptors, S1p(2)/LP(B2)/EDG-5 and S1P(3)/LP(B3)/EDG-3

Academic Article
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Overview

authors

  • Ishii, I.
  • Ye, X. Q.
  • Friedman, B.
  • Kawamura, S.
  • Contos, J. J. A.
  • Kingsbury, M. A.
  • Yang, A. H.
  • Zhang, G. F.
  • Brown, J. H.
  • Chun, Jerold

publication date

  • July 2002

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Five cognate G protein-coupled receptors (S1P(1-5)) have been shown to mediate various cellular effects of sphingosine 1-phosphate (S1P). Here we report the generation of mice null for S1P(2) and for both S1P(2) and S1P(3). S1P(2)-null mice were viable and fertile and developed normally. The litter sizes from S1P(2)S1P(3) double-null crosses were remarkably reduced compared with controls, and double-null pups often did not survive through infancy, although double-null survivors lacked any obvious phenotype. Mouse embryonic fibroblasts (MEFs) were examined for the effects of receptor deletions on S1P signaling pathways. Wild-type MEFs were responsive to S1P in activation of Rho and phospholipase C (PLC), intracellular calcium mobilization, and inhibition of forskolin-activated adenylyl cyclase. S1P(2)-null MEFs showed a significant decrease in Rho activation, but no effect on PLC activation, calcium mobilization, or adenylyl cyclase inhibition. Double-null MEFs displayed a complete loss of Rho activation and a significant decrease in PLC activation and calcium mobilization, with no effect on adenylyl cyclase inhibition. These data extend our previous findings on S1P(3)-null mice and indicate preferential coupling of the S1P(2) and S1P(3) receptors to Rho and PLC/Ca(2+) pathways, respectively. Although either receptor subtype supports embryonic development, deletion of both produces marked perinatal lethality, demonstrating an essential role for combined S1P signaling by these receptors.

subject areas

  • Adenylyl Cyclases
  • Animals
  • Base Sequence
  • Calcium
  • DNA Primers
  • DNA-Binding Proteins
  • Female
  • Genes, Lethal
  • I-kappa B Proteins
  • Litter Size
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophospholipid
  • Signal Transduction
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M200137200

PubMed ID

  • 12006579
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Additional Document Info

start page

  • 25152

end page

  • 25159

volume

  • 277

issue

  • 28

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