Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor.

Abstract

Sphingosine‐1‐phosphate (S1P) is a bioactive lysosphingolipid implicated in mitogenesis and cytoskeletal remodelling, but its mechanism of action is poorly understood. We report here that in N1E‐115 neuronal cells, S1P mimics the G protein‐coupled receptor agonist lysophosphatidic acid (LPA) in rapidly inducing neurite retraction and soma rounding, a process driven by Rho‐dependent contraction of the actin cytoskeleton. S1P is approximately 100‐fold more potent than LPA in evoking these shape changes, with an EC50 as low as 1.5 nM. Microinjection of S1P has no effect, neither has addition of sphingosine or ceramide. As with LPA, S1P action is inhibited by suramin and subject to homologous desensitization; however, the responses to S1P and LPA do not show cross‐desensitization. We conclude that S1P activates its own high affinity receptor to trigger Rho‐regutated cytoskeletal events. Thus, S1P and LPA may belong to an emerging family of bioactive lysophospholipids that act through distinct G protein‐coupled receptors to mediate similar actions.

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

“…Control cultures lacking primary antibody incubation showed no significant staining (d). Postma et al 1996). The effects of S1P in other systems have been related to control of cell proliferation and migration (Zhang et al 1990).…”

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

“…Therefore, whether the apoptotic effect of sphingosine observed in the present study represents a physiological or pharmacological action of this sphingolipid requires further characterization. In addition to their anti-tumour effects, sphingolipids also participate in the regulation of various physiological processes, including platelet aggregation, neutrophilmediated inflammatory responses and retraction of neurites in neuronal cells [47][48][49]. Therefore the characterization of specific signalling pathways triggered by specific sphingolipids is important for the understanding of the different biological function of sphingolipids.…”

Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

“…Furthermore, this agent has been shown to be a non-selective antagonist of G-protein-coupled receptors [14,15]. As shown in Figure 4 S1P-induced activation of ERK and p38 MAP kinase was competitively inhibited by suramin.…”

“…The cellular responses elicited by S1P have been ascribed to intracellular actions. On the other hand, S1P-induced responses are also accompanied by the stimulation of several early signalling events, which are usually regulated by cell-surface receptors [8][9][10][11][12][13][14][15][16]. These signalling events include activation of phospholipase C [8][9][10][11], an increase in cytoplasmic free Ca# + concentration [8][9][10][11][12][13]16], regulation of adenylyl cyclase [8,11,12], activation of K + channels [12] and activation of Rho [14,15].…”