Sphingosine signaling

G-protein-coupled receptors (GPCRs), although some of them additionally play a role in intracellular signal transduction. Sphingosine-1-phosphate (SIP) and... 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Pyne S, Pyne NJ 2000 Sphingosine 1-phosphate signalling in mammalian cells. Biochem J 349 385M02... 

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

This chapter describes the metabohsm of sphingosine and SIP, evidence to support their pro- and anti-apoptotic effects and their proposed sites of action on signaling processes that contribute to apoptosis and proliferation. 

A signaling rheostat has been proposed where the relative level of SIP and ceramide determines cellular fate. This was based on the observation that ceramide, Fas and TNFa-mediated programmed cell death is suppressed by the addition of SIP (Cuvillier et al, 1996). The model assumes that ceramide is a physiological mediator of apoptosis although this is subject to controversy (Hofmann and Dixit, 1998 Kolesnick and Hannun, 1999). Indeed, sphingosine is also implicated as an apoptotic agent (see above). 

An, S., Bleu, T. and Zheng, Y., 1999, Transduction of intracellular calcium signals through G protein- mediated activation ofphosphohpase C by recombinant sphingosine 1- phosphate receptors. Mol. Pharmacol. 55 787-794. 

An, S., Goetzl, E.J. and Lee, H., 1998, Signaling mechanisms and molecular characteristics of G protein-coupled receptors for lysophosphatidic acid and sphingosine 1-phosphate. J. 

Choi, O.H., Kim, J.H. and Kinet, J.P., 1996, Calcium mobihsation via sphingosine kinase in signaling by the FceRI antigen receptor. Nature (London) 380 634-636. 

Durieux, M.E., Carlisle, S.J., Salafranca, M.N. and Lynch, K.R., 1993, Responses to sphingosine-1 -phosphate in X. laevis oocytes Similarities with lysophosphatidic add signaling. Am. J. Physiol. 264 C1360-C1364. 

Sillard, R., Harii, K. and Takuwa, Y., 1999, The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and -insensitive G-proteins to multiple signaling pathways. Biochem. J. 337 67-75. 

Ishizuka, T., Murata, N., Kanda, T., Kobayashi, I., Ohta, H., Ui, M. and Okajima, F., 1999, Comparison of intrinsic activities of the putative sphingosine 1-phosphate receptor sub-types to regulate several signaling pathways in their cDNA-transfected Chinese hamster ovary cells. J. Biol. Chem. 274 23940-23947. 

Meyer zu Heiingdoif, D.M., Lass, H., Alemany, R., Laser, K.T., Neumann, R, Zhang, C., Schmidt, M., Rauen, Lf., Jakobs, K.H. and Van Koppen, C.J., 1998, Sphingosine kinase-mediated signaling by G-protein-coupled receptors, EMBO J. 17 2830-2837. 

Pyne, S. and Pyne, N.J., 2000, Sphingosine 1-phosphate signaling in mammalian cells, Biochem. J. 349 385 2. 

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