Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS

Terai, Kazuhiro; Soga, Tsunehiko; Takahashi, Masanori; Kamohara, Masazumi; Ohno, Kousaku; Yatsugi, Shin-ichi; Okada, Michiyo; Yamaguchi, Takashi

doi:10.1016/s0306-4522(02)00791-1

Cited by 91 publications

(78 citation statements)

References 41 publications

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“…This is in contrast to the finding of Terai et al (2003), who reported Edg8/S1P5 protein expressed by NG2-positive OPCs but not mature oligodendrocytes. Under our experimental conditions, we showed, by both in situ hybridization and immunolabeling, the expression of Edg8/S1P5 in mature oligodendrocytes of the mouse brain.…”

Section: Discussioncontrasting

confidence: 99%

“…Under our experimental conditions, we showed, by both in situ hybridization and immunolabeling, the expression of Edg8/S1P5 in mature oligodendrocytes of the mouse brain. In agreement with the report of Terai et al (2003), we were also able to detect Edg8/S1P5 expression on pre-oligodendrocytes and the majority of OPCs. These data are consistent with an expression of Edg8/S1P5 throughout oligodendroglial development.…”

Section: Discussionsupporting

confidence: 92%

“…At the cellular level, Edg2/ LPA1 has been shown to be expressed on mature oligodendrocytes (Allard et al, 1998;Cervera et al, 2002;Stankoff et al, 2002b), whereas its expression on immature oligodendrocytes remains controversial (Moller et al, 1999;Dawson et al, 2003). Immunohistochemical analysis has suggested that Edg8/S1P5 is expressed in NG2-positive OPCs but not in mature oligodendrocytes (Terai et al, 2003), whereas expression of Edg8/S1P5 transcripts has been detected by reverse transcription (RT)-PCR in differentiated rat oligodendrocytes in culture (Yu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

Jaillard

Harrison²,

Stankoff³

et al. 2005

J. Neurosci.

312

276

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Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

Jaillard

Harrison²,

Stankoff³

et al. 2005

J. Neurosci.

312

276

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“…The mRNA for S1P5 is predominantly expressed in the white matter tracts of the brain, including the cerebellum, corpus callosum, and the spinal cord. [14][15][16][17][18][19] S1P5 receptors are preferentially expressed in oligodendrocytes at all stages of development: progenitors and mature lineages. [9,17,20] The distinct distribution pattern of S1P5 suggests it may play an important role in regulating myelination.…”

Section: Compoundsmentioning

confidence: 99%

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

et al. 2010

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The immunomodulatory drug fingolimod (FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), derived from a fungal metabolite myriocin), is phosphorylated in vivo by sphingosine kinases to produce (R)-FTY720-phosphate (FTY720-P). [1,2] FTY720-P activates sphingosine-1-phosphate (S1P) receptors S1P1, S1P3, S1P4, and S1P5 at low nanomolar concentrations and is inactive toward the S1P2 receptor.[1] The FTY720-P-mediated activation of the S1P1 receptor on lymphocytes induces receptor internalization, which attenuates T-cell response to S1P gradients, preventing their egress from secondary lymphoid tissues. [3] In addition to playing a role in the immune system, all S1P receptors except S1P4 are also found differentially expressed in the central nervous system [4] and on various tumor cell types. [5,6] Although the precise regulation of these receptors by locally released S1P remains unclear, S1P receptors are thought to play a role in such events as astrocyte migration, [7] oligodendrocyte differentiation, and cell survival [8,9] and neurogenesis. [10,11] To assess the relevance of individual S1P receptor subtypes for the activity of FTY720-P, selective agonists are required. Because S1P5 receptors are expressed on oligodendrocytes, and S1P5 receptors are thought to play a role in oligodendrocyte differentiation and survival, we focused on the development of S1P5 agonists. By using a highthroughput screening calcium mobilization assay with GPCR priming and FLIPR technology, [12] we discovered benzamide 1, which has good in vitro potency toward the S1P5 receptor (EC 50 = 270 nm), but has modest selectivity against S1P1 (EC 50 = 3140 nm) and S1P4 (EC 50 = 100 nm). Herein we report our studies of various benzamide modifications carried out to improve the selectivity, bioactivity, pharmacokinetic properties, and ancillary profile of 1, ultimately resulting in the discovery of potent and very selective S1P5 agonists.To guide the optimization process, homology models of all S1P receptors were built from a crystal structure of bovine rhodopsin (PDB ID: 1F88). [13] Docking experiments of 1 into these models revealed a possible location of the binding site, some essential features of the interactions, and indicated potential regions for gaining selectivity and improving potency. In these complexes (Figure 1), 1 adopts a twisted conformation with the aniline ring,~708 out of the benzamide plane and stabilized by a hydrogen bond between the aniline NH group and the amide carbonyl. In the S1P5 receptor complex, the amide group forms a hydrogen bond with OG1-Thr120. The benzamide phenyl ring lies in a large hydrophobic pocket surrounded by Phe196, Phe201, Phe268, Leu119, Trp264, Leu267, and Leu271. The aniline ring undergoes a T-shaped interaction with Phe116 and hydrophobic contacts with Leu271 and Leu292. The ortho-methyl substituents fill a small pocket formed by Tyr89, Val115, and Leu292 on one side, and sit at the face of Phe196 on the other side. Inspection of sequence alignments (Figure 2) revealed two positions, o...

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“…S1P 4 -deficient mice have not yet been described, but a role for this receptor in regulation of T-cell cytokine production has been proposed (Wang et al, 2005). S1P 5 is expressed primarily in the white matter tracts of the central nervous system with the highest levels in oligodendrocytes, the myelinating cells of the brain (Im et al, 2000;Terai et al, 2003). S1P 5 -deficient immature oligodendrocytes display reduced responses to S1P in vitro; however, no deficits in myelination were observed in S1P 5 -deficient mice (Jaillard et al, 2005).…”

Section: Sphingosine 1-phosphate Receptorsmentioning

confidence: 99%