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Gene Review

S1pr5  -  sphingosine-1-phosphate receptor 5

Rattus norvegicus

Synonyms: Edg-8, Edg8, Endothelial differentiation G-protein-coupled receptor 8, NRG-1, Nerve growth factor-regulated G-protein-coupled receptor 1, ...
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Disease relevance of Edg8

  • In a rat hepatoma Rh7777 cell line that exhibits modest endogenous responses to sphingosine 1-phosphate, this lipid mediator inhibited forskolin-driven rises in cAMP by greater than 90% when the cells were transfected with Edg-8 DNA (IC(50) 0.7 nm) [1].
  • We investigated the expression of the Nrg-1 type I in rat embryo dorsal root ganglion (DRG) neurons [2].
  • Synapse-specific and Nrg-1-induced AChR transcription require an enhancer sequence, the N-box, which is also mutated in some patients with congenital myasthenia gravis [3].
  • These results indicated that different NRG-1 levels are expressed upon nerve degeneration and the balance between those levels and other neurotrophic factors could have an important role on nerve regeneration [4].
  • We have previously demonstrated that neuregulin-1 (NRG-1) is upregulated and is neuroprotective in ischemic brain injury, however the expression and localization of its receptors during ischemia has not been investigated [5].

High impact information on Edg8

  • We find that IGF-I, like NRG-1, can prevent the apoptotic death of postnatal rat Schwann cells cultured under conditions of serum withdrawal [6].
  • This regulation is mediated in part by the provision of limiting axon-derived trophic molecules, although neuregulin-1 (NRG-1) is the only trophic factor shown to date to support Schwann cell survival [6].
  • Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, has been shown to be indispensable for the normal function of the adult heart by binding to ErbB4 receptors on cardiomyocytes [7].
  • Cardiac NRG-1 synthesis occurs in endothelial cells adjacent to cardiac myocytes and is sensitive to factors related to the regulation of blood pressure [7].
  • In rat CMVE in culture, NRG-1 mRNA and protein expression was down-regulated by angiotensin II and phenylephrine and up-regulated by endothelin-1 and mechanical strain [7].

Biological context of Edg8

  • 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 [8].
  • Using a similar sequence that we found in the expressed sequence tag data base, we cloned and characterized of a fourth, high affinity, rat brain sphingosine 1-phosphate receptor, Edg-8 [1].
  • In addition, in view of our previously described anti-adrenergic effects of NRG-1, we have studied which neurohormonal stimuli affect endothelial NRG-1 expression and release and how this may fit into a broader frame of cardiovascular physiology [7].
  • These studies demonstrate that the effects of NRG1 on beta2 subunit polypeptide expression require activation of the ErbB4 receptor tyrosine kinase; its effects are inhibited by pharmacological blockade of ErbB4 phosphorylation or reduction of receptor level with an antisense oligodeoxynucleotide [9].
  • Overall, our results provide some morphological and biochemical bases for explaining the effectiveness of fresh muscle-vein combined nerve guides and throw an interesting light on the possible role of alpha(2a-2b) NRG1 through the erbB2/erbB3 heterodimer receptor for nerve regeneration inside non-nervous conduits [10].

Anatomical context of Edg8

  • 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 [8].
  • Membranes from HEK293T and Rh7777 cell cultures expressing Edg-8 exhibited high affinity (K(D) = 2 nm) binding for radiolabeled sphingosine 1-phosphate [1].
  • Furthermore, Xenopus oocytes exhibit a calcium response to sphingosine 1-phosphate after injection of Edg-8 mRNA, but only when oocytes are co-injected with chimeric G(q/i)alpha protein mRNA [1].
  • CMVE-derived NRG-1 was shown to phosphorylate cardiomyocyte ErbB2, an event prevented by a 24-h preincubation of myocytes with monoclonal ErbB2 antibodies [7].
  • Immunohistochemical staining of rat heart and aorta showed that NRG-1 expression was restricted to the endocardial endothelium and the cardiac microvascular endothelium (CMVE); by contrast, NRG-1 expression was absent in larger coronary arteries and veins and in aortic endothelium [7].

Associations of Edg8 with chemical compounds

  • METHODS AND RESULTS: NRG-1 (alpha and beta isoforms) induced a negative inotropic effect in isolated rabbit papillary muscles and a rightward shift of the dose-response curve to isoproterenol [11].

Analytical, diagnostic and therapeutic context of Edg8

  • Rat Edg-8 RNA is expressed in spleen and throughout adult rat brain where in situ hybridization revealed it to be associated with white matter [1].
  • The nuclear localization of NRG-1 isoforms and/or erbB receptors in both cell types was confirmed by Western blotting of nuclear and cytoplasmic extracts [12].
  • Nrg-1 type I mRNA was abundantly expressed in DRG neurons; molecular cloning identified three distinct isoforms [2].
  • RT-PCR analysis verified the presence of all three types of NRG-1 mRNAs and their receptors in both types of nerves [4].
  • Real-time quantitative PCR (QPCR) assays showed that the relative expression levels of all three types of NRG-1 mRNAs were higher in optic nerves than in sciatic nerves [4].


  1. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. Im, D.S., Heise, C.E., Ancellin, N., O'Dowd, B.F., Shei, G.J., Heavens, R.P., Rigby, M.R., Hla, T., Mandala, S., McAllister, G., George, S.R., Lynch, K.R. J. Biol. Chem. (2000) [Pubmed]
  2. Neuregulin isoforms in dorsal root ganglion neurons: effects of the cytoplasmic domain on localization and membrane shedding of Nrg-1 type I. Zhang, Z., Prentiss, L., Heitzman, D., Stahl, R.C., DiPino, F., Carey, D.J. J. Neurosci. Res. (2006) [Pubmed]
  3. Stimulation of acetylcholine receptor transcription by neuregulin-2 requires an N-box response element and is regulated by alternative splicing. Ponomareva, O.N., Ma, H., Dakour, R., Raabe, T.D., Lai, C., Rimer, M. Neuroscience (2005) [Pubmed]
  4. A real-time quantitative PCR comparative study between rat optic and sciatic nerves: determination of neuregulin-1 mRNA levels. Martínez, J.C., Malavé, C., Bosch, I., Castillo, C., Núñez, J., Villegas, G.M., Villegas, R. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  5. Upregulation of erbB receptors in rat brain after middle cerebral arterial occlusion. Xu, Z., Ford, B.D. Neurosci. Lett. (2005) [Pubmed]
  6. A role for insulin-like growth factor-I in the regulation of Schwann cell survival. Syroid, D.E., Zorick, T.S., Arbet-Engels, C., Kilpatrick, T.J., Eckhart, W., Lemke, G. J. Neurosci. (1999) [Pubmed]
  7. Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. Lemmens, K., Segers, V.F., Demolder, M., De Keulenaer, G.W. J. Biol. Chem. (2006) [Pubmed]
  8. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. Jaillard, C., Harrison, S., Stankoff, B., Aigrot, M.S., Calver, A.R., Duddy, G., Walsh, F.S., Pangalos, M.N., Arimura, N., Kaibuchi, K., Zalc, B., Lubetzki, C. J. Neurosci. (2005) [Pubmed]
  9. Neuregulin induces GABAA receptor beta2 subunit expression in cultured rat cerebellar granule neurons by activating multiple signaling pathways. Xie, F., Raetzman, L.T., Siegel, R.E. J. Neurochem. (2004) [Pubmed]
  10. Schwann cell behavior after nerve repair by means of tissue-engineered muscle-vein combined guides. Raimondo, S., Nicolino, S., Tos, P., Battiston, B., Giacobini-Robecchi, M.G., Perroteau, I., Geuna, S. J. Comp. Neurol. (2005) [Pubmed]
  11. Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Lemmens, K., Fransen, P., Sys, S.U., Brutsaert, D.L., De Keulenaer, G.W. Circulation (2004) [Pubmed]
  12. Localization of neuregulin isoforms and erbB receptors in myelinating glial cells. Raabe, T.D., Deadwyler, G., Varga, J.W., Devries, G.H. Glia (2004) [Pubmed]
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