Selective Loss of Sphingosine 1-Phosphate Signaling with No Obvious Phenotypic Abnormality in Mice Lacking Its G Protein-coupled Receptor, LP B3/EDG-3

Isao Ishii, Beth Friedman, Xiaoqin Ye, Shuji Kawamura, Christine McGiffert, James J.A. Contos, Marcy A. Kingsbury, Guangfa Zhang, Joan Heller Brown, Jerold Chun

Research output: Contribution to journalArticlepeer-review

231 Citations (Scopus)

Abstract

Sphingosine 1-phosphate (S1P) exerts diverse physiological actions by activating its cognate G protein-coupled receptors. Five S1P receptors have been identified in mammals: LPB1/EDG-1, LP B2/H218/AGR16/EDG-5, LPB3/EDG-3, LP B4/NRG-1/EDG-8, and LPC1/EDG-6. One of these receptors, LPB1, has recently been shown to be essential for mouse embryonic development. Here we disrupted the lPB3 gene in mice, resulting in the complete absence of lPB3 gene, transcript, and LPB3 protein. LPB3-null mice were viable and fertile and developed normally with no obvious phenotypic abnormality. We prepared mouse embryonic fibroblast (MEF) cells to examine effects of LPB3 deletion on S1P-induced signal transduction pathways. Wild-type MEF cells expressed lP B1, lPB2, and lPB3 but neither lPB4 nor lPC1, and they were highly responsive to S1P in phospholipase C (PLC) activation, adenylyl cyclase inhibition, and Rho activation. Identically prepared LPB3-null MEF cells showed significant decreases in PLC activation, slight decreases in adenylyl cyclase inhibition, and no change in Rho activation. Retrovirus-mediated rescue of the LPB3 receptor in LPB3-null MEF cells restored S1P-dependent PLC activation and adenylyl cyclase inhibition. These results indicate a nonessential role for LPB3 in normal development of mouse but show nonredundant cellular signaling mediated by a single type of S1P receptor.

Original languageEnglish
Pages (from-to)33697-33704
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number36
DOIs
Publication statusPublished - 2001 Sep 7

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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